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TITLE: A Fall Prevention Program for High Risk Elderly Women NINR
P.I.: Jean F. Wyman, Ph.D., R.N.
INSTITUTION: University of Minnesota, Minneapolis, MN
GRANT NO.: 1R01NR05107-01
KEYWORDS: injury prevention, nursing intervention, clinical research
TYPE STUDY: Clinical
AMOUNT: $150,000
The long term objective of this study is to develop cost-effective, community-based strategies for the prevention of falls in high risk elderly women. Specific aims: 1) Test the efficacy of a fall prevention program for high risk elderly women on fall rates over one and two years; 2) Determine the effects of the fall prevention program on postural competence, functional performance, and a variety of other outcome measures; and 3) Identify demographic, clinical, personal, functional, and postural competence variables that predict long-term exercise adherence for participants in the fall prevention program. The participants will be 250 community-dwelling women who are aged 70 and over, mentally intact, ambulatory, with postural instability and at least one other fall risk factor, not currently involved in regular exercise, and medically stable with physician approval for independent exercise participation. This study will provide information on the efficacy and cost of simple interventions designed to prevent falls and fall-related injuries, reduce preclinical disability, maintain long-term exercise adherence, and improve quality of life for older women.
TITLE: Estrogen and Cholinergic System Interactions in Aging NIA
P.I.: Sonsoles de Lacalle, M.D., Ph.D.
INSTITUTION: Beth Israel Deaconess Medical Center, Boston, MA
GRANT NO.: 1R01AG19597-01
KEYWORDS: Neurobiology, estrogen, Alzheimer's disease
TYPE STUDY: Basic
AMOUNT: $100,000
This study will explore the effects of estrogen on cholinergic neuron sprouting and function in a rat lesion model that mimics some of the cholinergic deficits associated with Alzheimer disease. Following lesioning of the cholinergic input to the entorhinal cortex with a specific immunotoxin, the ability of estrogen to promote growth and arborization of cholinergic fibers, to increase transcription of genes required for cholinergic neurotransmission, and to reduce lesion-induced cognitive behavioral deficits will be studied. A number of experimental studies have suggested that postmenopausal estrogen replacement therapy may be beneficial in reducing a woman risk of developing Alzheimer disease. However, such therapy remains a major concern for women and their doctors due to potential severe side effects of estrogen use, particularly breast cancer. The studies proposed in this grant application may contribute important information on the mechanistic link between estrogen, cognition, and Alzheimer disease in older women, and promote further interest in designing better therapeutic strategies, including development of estrogenic compounds specific for neural tissues.
TITLE: Postmenopausal Estrogen Influences on Olfaction NIA
P.I.: Richard Doty, Ph.D.
INSTITUTION: University of Pennsylvania, Philadelphia, PA
GRANT NO.: 1R01AG17496-01A1
KEYWORDS: Postmenopausal, hormone replacement therapy, olfaction, cognition
TYPE STUDY: Clinical
AMOUNT: $100,000
Declines in both olfactory and cognitive function are known to occur during the aging process, and are predictive for dementia. Some evidence exists that both of these functions can be improved by the use of hormone replacement therapy (HRT) in postmenopausal women. This study will test the hypothesis that HRT is associated with higher olfactory and cognitive functioning in postmenopausal women. Six hundred postmenopausal women will be studied retrospectively. Four types of odor tests will be conducted as well as a neuropsychological battery. Direct radioimmunoassay measurement of hormones will be performed, and other variables, such as, age, education, medications, etc. will be considered in the multi variate analysis. If HRT were found to benefit olfaction and cognition in postmenopausal women, improvements in both nutritional and functional status could result.
TITLE: Vascular Gene Expression in Aging Women NIA
P.I.: Thomas Register, Ph.D.
INSTITUTION: Wake Forest University School of Medicine, Winston-Salem, NC
GRANT NO.: 1R03AG18170-01
KEYWORDS: cardiovascular, microarray analysis, estrogens
TYPE STUDY: Basic
AMOUNT: $72,500
Estrogen replacement therapy has been shown to reduce the incidence of CHD in post-menopausal women, and to inhibit the progression of diet-induced atherosclerosis in ovarectomized animal models. Only a portion of the protective effect can be explained by alterations in traditional risk factors, and increasing evidence demonstrates that direct actions of estrogen on the artery are important in this protection. However, the cellular and molecular mechanisms of estrogen action on the artery are poorly defined. Estrogen receptors are present in vascular beds and cells, demonstrating the potential for estrogen to regulate vascular function through its specific receptors. Estrogen receptors may regulate gene expression through 1) interactions with estrogen response elements in regulatory regions of target genes, or 2) interaction with other transcription factors, such as nuclear factor-kB (NF-kB), AP-1 (c-fos, c-jun), and PPAR-y. Thus, while there is potential for many genes to be regulated by estrogen, little is known regarding the range and depth of effects of estrogen on transcriptional events in vascular cells. Recently developed technologies allow the rapid and simultaneous screening of the mRNA levels for many target molecules of known function and provide an excellent method for determination of the breadth of estrogen effects. The central hypothesis of the proposed studies is that estrogen inhibits the initiation and progression of atherogenesis in part through direct estrogen receptor-dependent effects on vascular gene expression. The specific aims are to determine the direct effects of estrogen on transcriptional events in vascular smooth muscle and endothelial cells in order to gain insights into the progression of the disease as well as potential therapies to prevent this age-related disease.
TITLE: Progestogens vs Phytoestrogens: An Adjunct to ERT NIA
P.I.: James K. Williams, DVM
INSTITUTION: Wake Forest University School of Medicine, Winston-Salem, NC
GRANT NO.: 1R01AG17864-01
KEYWORDS: Estrogen replacement therapy, postmenopausal, alternative therapy
TYPE STUDY: Clinical
AMOUNT: $200,000
Postmenopausal estrogen replacement therapy (ERT) reduces morbidity and mortality from coronary heart disease (CHD). There is a continuing concern, however, that the concurrent use of a progestogen to protect the endometrium may reduce the cardiovascular benefits of ERT. This has stimulated interest in developing cardiovascular-safe (CV-safe) progestogens and/or alternative approaches to protect the endometrium and breast during estrogen replacement therapy. Progesterone does not diminish the cardiovascular benefits of ERT. However, it provides little or no additional beneficial effects on CV-risk, is associated with continued menstrual cycles and is not protective for the breast. Soy phytoestrogens (SPEs) may be an effective alternative approach to progestogen therapy. We have shown that SPEs have estrogen agonist effects on the cardiovascular system, but antagonize the effects of ERT on mammary and endometrial tissue. Furthermore, SPEs combine with ERT to have additive beneficial effects on the cardiovascular system and on preservation of bone density. Thus, we hypothesize that, because their estrogen agonist/antaponist properties, SPEs can obviate the need for progestogen therapy during ERT of postmenopausal females. The specific aims of this study are: 1) To assess the potential contribution of increasing doses of SPEs to the putative beneficial cardiovascular (plasma lipoprotein concentrations, carbohydrate metabolism, vascular reactivity, hemodynamics) and bone (plasma markers of bone metabolism) effects of ERT treatment in postmenopausal subjects; 2) To identify the dose of SPEs that protects the mammary and endometrial tissue from ERT-induced cell proliferation and hyperplasia; 3) To identify and compare the potential additive beneficial effects of SPEs with those of progestogen treatment (MPA or progesterone) on cardiovascular and bone endpoints in postmenopausal subjects receiving ERT; and 4) To measure and compare the effects of SPE administration with those of MPA and progesterone, on mammary and endometrial hyperplasia in postmenopausal subjects receiving ERT.
ALCOHOL AND OTHER SUBSTANCE ABUSE
TITLE: Alcohol, HIV Risk Behaviors, and Sexual Victimization NIAAA
P.I.: Maria Testa, PhD
INSTITUTION: Research Institute on Addictions, Buffalo, NY
GRANT NO.: 1R01AA12013-01A1
KEYWORDS: Risk behaviors, HIV, sexual victimization
TYPE STUDY: Clinical
AMOUNT: $100,000
This application suggests that childhood sexual abuse and risk-prone personality (high sensation-seeking, high negative affect, low assertiveness) lead women to engage in risky behaviors (heavy alcohol and drug use, high levels of sexual activity and exposure to risky settings such as bars) which in turn increase the likelihood of experiencing both sexual victimization and HIV/STD infections. There will be a three wave cross-legged panel design using a representative sample of 1,000 unmarried women, ages 18-30, recruited from random digit dialing.
TITLE: Sexual Identity and Drinking: Risk and Protect Factors NIAAA
P.I.: Tonda L. Hughes, PhD
INSTITUTION: University of Illinois at Chicago, IL
GRANT NO.: 1K01AA00266-01
KEYWORDS: Alcohol, lesbians
TYPE STUDY: Clinical
AMOUNT: $55,890
This study will use an existing survey instrument to examine and compare risk and protective factors for heavy drinking and alcohol-related problems in lesbians and heterosexual women. The study will include data from 600 women who are 18 years of age or older.
TITLE: Women with Schizophrenia & Co-Occurring Substance Use Disorders NIDA
P.I.: Dr. Jean Gearon
INSTITUTION: University of Maryland, MD
GRANT NO.: 1R29DA11199-01A1
KEYWORDS: Schizophrenia, substance abuse, co-occurring substance use, HIV, risk factors
TYPE STUDY: Clinical
AMOUNT: $20,000
The primary goals of this project are: 1) to determine if women with schizophrenia and co-occurring substance use disorders are more vulnerable to HIV (e.g., engage in more high risk behaviors) and violent victimization than either women with major depression and co-occurring substance use disorders or women with substance use disorders only and no history of serious and persistent mental illness; 2) to determine if women with schizophrenia who abuse substances experience more violent victimization than women with major depression and co-occurring substance use disorders, or women with substance abuse disorders alone and no history of serious and persistent mental illness, and 3) to examine the causal sequencing between cognitive functioning, social competency, negative symptoms and HIV risk and victimization.
TITLE: Effect on Maternal-Fetal Attachment in Heavy Drinkers NIAAA
P.I.: Marilyn W. Lewis, M.A.
INSTITUTION: Columbia University, New York, NY
GRANT NO.: 1F31AA05560-01
KEYWORDS: alcohol, pregnancy, depression, behavior
TYPE STUDY: Clinical
AMOUNT: $26,259
This fellowship will support a longitudinal study of maternal-fetal attachment of alcohol dependent women. Three main objectives will be evaluated: 1) the quality of prenatal attachment in alcohol using, abusing, and dependent women; 2) whether there is a relationship between attachment and discontinuation or reduction of alcohol use; and 3) which intervening variables mediate development of attachment and abstinence. Five hundred pregnant, multiparous women in their second trimester will be recruited. Inventories of alcohol and drug use, and maternal-fetal attachment will be obtained, and instruments which measure social support, stress, and psychological symptoms will be administered. Major hypotheses are: 1) a pregnant woman without a childhood history of abuse, will more likely attach to her fetus; 2) a pregnant alcohol abusing woman who experiences lower levels of stress and higher social support, from her mother and from the father-to-be will more likely attach to her fetus; 3) the presence of depression or anxiety will interfere with prenatal attachment; and 4) and a pregnant woman who becomes attached to her fetus will more likely discontinue or reduce alcohol use. Regression analysis will be used to determine whether attachment explains a significant amount of variance in the model over and above the mediating variables.
TITLE: Gender Differences in Drug Abuse NIDA
P.I.: Jill B. Becker, Ph.D.
INSTITUTION: University of Michigan, Ann Arbor, MI
GRANT NO.: 1R01DA12677-01A1
KEYWORDS: endocrine, cocaine, estrogen, drug self-administration, psychomotor behavior, neurobiology
TYPE STUDY: Basic
AMOUNT: $291,390
The experiments proposed will utilize well characterized animal models to study the neurobiological basis for gender differences in drug abuse. Neuroadaptations associated with sensitization to psychomotor stimulants are thought to play an important role in the process of addiction. Furthermore, gender differences in the behavioral and neurochemical effects of psychomotor stimulants have been repeatedly reported to occur in rodents, and more recently in humans as well. To understand gender differences in drug abuse, basic research on the role of gender and ovarian hormones in the response to acute and repeated exposure to cocaine is an important next step. Research on the acute behavioral response to psychomotor stimulants indicates that treatment of female rats with the ovarian hormone estrogen is sufficient to induce changes comparable to the effects of the estrous cycle. Two hypotheses will be tested. The first is that there are gender differences in behavior induced by repeated exposure to the psychomotor stimulants and gender differences in self-administration of cocaine. The second is that estrogen potentates both the acute and sensitized response to cocaine in female rats, enhancing these gender differences. To understand the underlying neurological bases for gender differences in cocaine addiction, two important factors will be examined: 1) differences between males and females (independent of gonadal hormones); and 2) whether gonadal hormones in either males or females affect responses to cocaine. In humans these factors are intermingled because chronic cocaine use can disrupt and even cause cessation of a woman menstrual cycle. In such women, estrogen may play a role in acquisition of drug taking behaviors, but not in maintenance of these behaviors (since in women with amenorrhea the serum concentrations of estrogen are extremely low). However, more men than women abuse drugs, and many boys begin using drugs prior to sexual maturation. The experiments proposed will allow elucidation of the relative importance of gender vs gonadal hormones in animal studies investigating the effects on cocaine-induced psychomotor behavior and cocaine self-administration.
CANCER
TITLE: Clinical Trials of Two Human Papillomavirus (HPV)-like Particle NCI
P.I.: Douglas R. Lowy, M.D.
INSTITUTION: NCI, Bethesda, MD
GRANT NO.: 1Z01BC09052-09
KEYWORDS: Human papillomavirus, cancer, cervical, vaccine
TYPE STUDY: Clinical
AMOUNT: $500,000
This project will perform the early phase clinical trials of two HPV16-based papillomavirus vaccines. L1 is a major structural papilloma viral protein that can self-assemble into virus-like particles (VLPs). It is thought that L1 VLP will only protect by preventing primary infection. To add another level of protection, a chimeric VLP was developed by adding the L2 minor capsid protein to the L1. After preclinical vaccine results, an early phase human trial of L1 HPV16 VLP vaccine is being tested. There are four groups of 12 normal volunteers 18-29 years old. In each group, ten volunteers received the vaccine and two received a placebo in a double-blind fashion.
TITLE: Role and Functions of Pyrimidines in Cancer Therapy NCI
P.I.: Giuseppe Pizzorno, Ph.D., Pharm.D.
INSTITUTION: Yale University School of Medicine, New Haven, CT
GRANT NO.: 2R01CA67035-04A2
KEYWORDS: breast neoplasm, UPase gene
TYPE STUDY: Clinical
AMOUNT: $81,580
This investigator has uncovered a series of differences between normal and tumor cells in the control and regulation of uridine levels that can be exploited to achieve more selective cytotoxicity in tumors, better protection of normal tissues that are primary targets of fluoropyrimidine toxicity, and thereby to improve the therapeutic index of 5-fluorouracil. He has uncovered, in a set of 20 patients, a series of differences in the utilization and catabolism of uridine specific for human breast neoplasms: Uridine phosphorylase (UPase) is elevated 2-3 fold in tumor compared to paired normal tissues; in breast tumors 40-50% of total phosphorolytic activity is insensitive to a specific UPase inhibitor benzylacyclouridine (BAU). These variations are linked to two specific mutations in the structural and the regulatory domains of UPase gene. The investigator will develop a time line for their appearance, by studies of tissues from putative precursor stages such as ductal and atypical hyperplasia to locally advanced and metastatic tumors, to establish at which stage of tumor promotion or progression the UPase mutations become apparent.
DIABETES
TITLE: Diabetes Prevention Program (DPP) NIDDK
P.I.: Abbas Kitabchi, M.D.
INSTITUTION: University of Tennessee
GRANT NO.: 1R01DK53061-01
KEYWORDS: diabetes, noninsulin dependent diabetes mellitus, impaired glucose tolerance
TYPE STUDY: Clinical
AMOUNT: $200,000
The Diabetes Prevention Program (DPP) is a multi-centered randomized trial designed to determine whether type 2 diabetes can be prevented or delayed in a population of high-risk individuals. Included in the high-risk population are women with a history of GDM and individuals with impaired glucose tolerance. There are 3.234 participants enrolled in the three-arm study with two active treatment groups (metformin and life-style) compared to placebo controls. Of the total recruited, 68% were women, 13% of these had a history of GDM, and nearly 50% were from minority populations.
TITLE: Pathogenesis of Type II Diabetes in Latino Women NIDDK
P.I.: Thomas Buchanan, M.D.
INSTITUTION: University of Southern California School of Medicine, Los Angeles, CA
GRANT NO.: 3R01DK46374-08S1
KEYWORDS: prevention, gestational diabetes, clinical trial, Hispanic Americans
TYPE STUDY: Clinical
AMOUNT: $200,000
This study is to support a follow-up study on 237 Hispanic women with a history of gestational diabetes mellitus who are at high risk for type 2 diabetes. These at-risk individuals were in an intervention trial that tested whether an insulin-sensitizing agent could prevent or delay the onset of type 2 diabetes. The study results indicate that intervention with active drug compared to placebo reduced diabetes onset by 50%. The conclusion of this study has resulted in a cohort of women whose incidence of diabetes has been dramatically reduced for a median of 27 months and who are now off drug treatment. A critical question is, what is the effect of past diabetes prevention on current risk of diabetes. It is hypothesized that a reduction in the ability of the beta cell to produce enough insulin to compensate for insulin resistance in the high-risk women leads to diabetes. Conversely, preservation of beta cell function may decrease the risk of type 2 diabetes. This proposal is designed to determine 1) the impact of long-term improvement of insulin sensitivity on beta cell function, and 2) to address whether administration of a drug used to control blood sugar is masking the underlying biology of diabetes onset. The results will be of major value in understanding the outcomes of the NIDDK Diabetes Prevention Program, a multi centered randomized study to determine whether type 2 diabetes can be prevented or delayed in a population of high-risk individuals.
TITLE: Family-Centered Diabetes Project NIDDK
P.I.: Janette Carter, M.D.
INSTITUTION: University of New Mexico Health Science Center, Albuquerque, NM
GRANT NO.: 3R01DK47096-06S1
KEYWORDS: diabetes, behavioral research, prevention, nutrition, physical activity, American Indians
TYPE STUDY: Clinical
AMOUNT: $100,000
Diabetes prevention among young Native American women will be studied by concentrating on modifiable risk factors. Young Native American women are considered important recipients of diabetes prevention activities because of their pivotal role in the family environment, being the primary care givers for their children and families. In addition, young women are themselves at high risk for the development of diabetes, including gestational diabetes. It is the long-range goal of the 'Family-Centered Diabetes Project' to reduce modifiable diabetes risk factors in Native American women and their families through a culturally specific intervention. The specific aim of this study is to determine whether a lifestyle intervention program 'Sharing Wisdom', delivered to young Native American women without diabetes will reduce diabetes risk factors. The primary outcome measures are decreased fat in the diet, increased vegetable consumption, increased physical activity, and increased percentage of participants interested in breast feeding future children for at least two months. The secondary measures include decreased weight, improved physical fitness, decreased body fat, and decreased insulin levels. The study will be a randomized controlled design using an intervention and a control group. Outcome measures will be made at baseline, 6 months and one year.
TITLE: A New Approach for the Prevention and Treatment of Type I Diabetes NIDDK
P.I.: Sophia Casares, Ph.D.
INSTITUTION: Mount Sinai School of Medicine, New York, NY
GRANT NO.: 1R55DK55744-01A1
KEYWORDS: diabetes, autoimmune disease, genetic engineering
TYPE STUDY: Basic
AMOUNT: $100,000
Type I diabetes (insulin-dependent diabetes mellitus, IDDM) is characterized by low or absent levels of endogenously produced insulin, as a consequence of the autoimmune destruction of pancreatic 
-cells. The US incidence of IDDM in children up to 14-year old is estimated in the range of 12 to 20 per 100,000, with an increasing incidence worldwide. At present, there is no effective therapy to prevent or cure the disease in humans. The investigator has genetically engineered a dimeric MHC class II (I-Ed)/Fc, namely DEF, molecule containing a CD4 T cell epitope (HA110-120) of hemagglutinin (HA) of influenza A/PR/8/34 virus. DEF molecule exerts different immunomodulatory effects on the specific T cells depending on the dose: low doses polarize resting and activated T cells toward Th2 phenotype, and high doses induce central tolerance and peripheral anergy. The investigator proposes to evaluate the protective and curative capacity of DEF in an animal model for autoimmune diabetes. The animal model consists in double transgenic (dTg) mice expressing HA of influenza virus in the pancreatic -cells, and at the same time the specific T cell receptor (TCR-HA) for the immunodominant epitope HA110-120. The dTg mice develop insulitis, hyperglycemia, and hypoinsulinemia early in life. Researchers will investigate the immunomodulatory mechanisms responsible for the prophylactic and curative capacity of low and high doses of DEF in dTg mice. Human DEF-like molecules may represent a new approach for the prevention and treatment of Type I diabetes.
ENDOCRINOLOGY
TITLE: Regulation of Estrogen-Responsive Genes NICHD
P.I.: Dr. Marilyn Evans
INSTITUTION: West Virginia University School of Medicine, WV
GRANT NO: 2RO1HD26339
KEYWORDS: Estrogen, estrogen-responsive genes, transcription, vitellogenin, apolipoproteins
TYPE STUDY: Basic
AMOUNT: $30,000
The long-term objective of this research is to understand the molecular basis by which estrogen regulates the transcription of genes. The avian liver provides a model system in which estrogen-responsive genes direct the synthesis of egg yolk pre- cursor proteins. The specific aims of this proposal are to 1) define the estrogen-dependent chromatin alterations and transcription response of the vitellogenin (VT-II) gene, 2) determine the characteristics of the secondary response of apolipo- proteins (apo-II) and VT-II to estrogen, and 3) isolate and characterize mRNAs that are altered during the response to estrogen. The techniques that will be relied on are run-on transcription assays, in vivo foot printing and subtractive cloning techniques.
TITLE: Hormone Replacement and Cerebral Glucose Metabolism NIA
P.I.: John Woodard, Ph.D.
INSTITUTION: Georgia State University, Atlanta, GA
GRANT NO.: 1R55AG19615-01
KEYWORDS: estrogen, progestins, PET, postmenopausal, cognition
TYPE STUDY: Clinical
AMOUNT: $100,000
There is compelling evidence that estrogen replacement therapy (ERT) in postmenopausal women may preserve and improve cognition in demented and non-demented women. Epidemiological studies have suggested that ERT may reduce the risk of developing Alzheimer disease, and ERT may slow cognitive decline in demented women. In women without dementia, higher serum estradiol levels have been associated with better memory performance. However, some studies have suggested that progestins may actually alternate or reverse many cognitive benefits of estrogens. Neither the mechanisms by which ERT may produce beneficial cognitive effects nor the manner by which progestins could moderate the beneficial effects of estrogen are well-understood. Recent scientific interest has been directed toward investigating estrogen effects on glucose transport and utilization within the central nervous system (CNS). Given that glucose is the primary energy source of the brain, that impaired glucose transport promotes ATP depletion and compromise of a number of energy-dependent processes (particularly in synapses), and that estrogen exerts widespread cellular and behavioral effects on the CNS, the relationships between estrogen, glucose metabolism, and CNS functioning appear particularly compelling. It is not known whether ERT may produce an increase in global cerebral metabolic rate of glucose utilization (CMRglc) in humans or whether there are specific regional CMRglc increases that may modulate enhanced cognitive functioning. In this study, a three-arm, randomized, double blind study is proposed of the effects of a 6-month intervention period of conjugated equine estrogen (CEE) alone, CEE plus medroxprogesterone acetate (MPA), and placebo on modulation of global and regional CMRglc in healthy, cognitively intact postmenopausal women aged 60 to 65 years, inclusive. All participants will undergo pre- and post-intervention dynamic FDG-PET studies of CMRglc. The two intervention groups will include 20 women without and 20 with a uterus, respectively, and the placebo group will contain 10 women without and 10 with a uterus. FDG PET will be used to accomplish the following specific aims: 1) to determine whether ERT produces increases in global and/or regional CMRglc after 6 months by comparing hysterectomized women on ERT versus placebo; 2) to determine whether progestin-estrogen replacement therapy (PERT) produces increases in global and/or regional CMRglc after 6 months by comparing women with a uterus on PERT versus placebo; and 3) to determine whether PERT produces a different pattern or magnitude of global and/or regional CMRglc after 6 months compared to ERT.
TITLE: Psychobiology of Estrogen Receptor Modulators NICHD
P.I.: Mark E. Wilson, Ph.D.
INSTITUTION: Emory University, Atlanta, GA
GRANT NO.: 1R01HD38917-01
KEYWORDS: Selective Estrogen Receptor Modulators (SERMs), reproductive health, neurobiology, behavior
TYPE STUDY: Basic
AMOUNT: $100,000
Estrogens play an important role in maintaining bone density and cardiovascular health, which is the basis for treatment in postmenopausal women. However, traditional estrogen therapy may increase the risk of breast or uterine cancers. Selective estrogen receptor modulators (SERMs) were developed that can target specific estrogen sensitive tissues. Despite the increasing use of SERMS, and while the effects of SERMs on peripheral tissue are better understood, their activity within the CNS has not been fully explored. The investigator will focus on whether SERMs, specifically tamoxifen and raloxifene, act as estrogen agonists or antagonists within the CNS. Studies suggest that CNS neurochemical mechanisms are important in regulating social behavior. Three specific aims will be pursued: 1) an investigation of the effects of SERMs on affiliative and aggressive behaviors in female rhesus monkeys; 2) an examination of the effects of SERMs on female sexual behavior and the hypothalamic-pituitary-adrenal axis; and 3) a research on the effects of SERMs on the response of rhesus monkeys to stress. This study may support the growing body of evidence, based on animal models, indicating a number of neurobiological mechanisms through which estrogens may exert neuroprotective and neurotrophic effects on the CNS. Ultimately these data could provide a better understanding of the neurobiology of SERMS and their impact on behavioral health.
TITLE: Novel Inhibitors of Nuclear Receptor Function NIDDK
P.I.: Rodney Guy, Ph.D.
INSTITUTION: University of California, San Francisco
GRANT NO.: 1R55DK58080-01
KEYWORDS: endocrinology cancer, diabetes, osteoporosis, receptor inhibition
TYPE STUDY: Basic
AMOUNT: $100,000
The broad, long-term objectives of this proposal are the development of novel inhibitors that specifically prevent the interaction of nuclear receptors with their coactivating proteins through their NR box binding site and thus block functionally transcriptional activation by nuclear receptors. The Specific Aims of this proposal are: 1) to use conformationally constrained peptide inhibitors of the interaction of the human thyroid receptor (hTR1) with the glucocorticoid receptor interacting protein 1 (GRIP1) to evaluate the structure-activity relationships of the individual leucine side chains of the LxxLL triad (NR box) of GRIP1; 2) to design and synthesize sets of non-peptide compounds that mimic the side chain presentation of the LxxLL triad in order to establish a lead compound that functionally inhibits the hTR*GRIP1 protein-protein interaction; 3 ) to expand the biochemical model systems under consideration to include the estrogen receptor (ER), androgen receptor (AR), and peroxisome proliferator-activated receptor (PPAR) thus allowing the study of the specificity of inhibition of the nuclear receptor coactivator interactions; 4) to synthesize large libraries of non-peptide inhibitors, based upon the lead compounds, and screen these to find specific inhibitors for each nuclear receptor coactivator interaction; and 5) to optimize any active inhibitors of nuclear receptor function for maximal potency against particular receptors and selectivity among receptors. The health relatedness of this project is that the new method of inhibiting nuclear receptor function has the potential to provide new therapies for diseases mediated by nuclear receptors which include cancer, cardiovascular disease, diabetes, and osteoporosis - diseases currently treated with drugs based upon hormone structure. The research design is the use of molecular design and combinatorial chemistry to develop non-peptide inhibitors. The methods to be used as chemical synthesis, biochemical screening, structure determination, molecular design, and cellular biology evaluation of physiological efforts.
TITLE: Helix Initiation and Estrogen Receptor-Alpha Activation NIDDK
P.I.: Debra Skafar, Ph.D.
INSTITUTION: Wayne State University, Detroit, MI
GRANT NO.: 1R01DK56934-01A1
KEYWORDS: osteoporosis, SERMS, cardiovascular, menopause
TYPE STUDY: Basic
AMOUNT: $100,000
Estradiol-17 (E2) is a pivotal molecule in reproduction, the cardiovascular system, the central nervous system, and bone remodeling in men and women. In women, the reduction of (E2) levels after menopause increases the incidence of cardiovascular disease, leads to reduction in bone density and increases risk of osteoporosis, causes vasomotor instability ("hot flashes"), as well as atrophy of the urogenital tract. Raloxifene, used for protection against osteoporosis, and tamoxifen, used to treat and prevent hormone-dependent breast cancer, have fewer proliferative effects than (E2) , and also contain bone density and a favorable lipid profile. However, neither compound replicates the entire spectrum of beneficial effects of (E2) , including those on the cardiovascular system, on vasomotor instability, and on urogenital atrophy. The molecular bases for these differing activities remain incompletely understood. Furthermore, the ability of estrogens having the A-ring hydroxyl group moved from the 3 positions to the 2 or the 4 position (2-hydroxyestratrien-17-ol and 4-hydroxyestratrien-17-ol) to exhibit strong antagonist activity, as well as induce cell- and promoter- specific responses, cannot be explained by the current mode for antagonist action. The investigator will test a model of ER structure/function relationships in which hydrophobic and hydrogen-bonding helix capping interactions at the start of helix 12 modulate the conformational changes of the receptor. The proposed research will manipulate this region of the receptor by mutation and by ligand-binding to probe the structure and the conformational changes of the ER, its interaction with coactivators and corepressors, and its ability to activate transcription. The hypotheses will be tested using a combination of site-directed mutagenesis of the receptor, circular dischroism, spectroscopy, and measurements of ligand-binding affinity and dissociation rate, stability, transactivation ability, and association with coactivators and corepressors. The proposed experiments will permit understanding of how ligand-binding leads to selective biological responses.
GASTROENTEROLOGY
TITLE: Biofeedback for Fecal Incontinence and Constipation NIDDK
P.I.: William E. Whitehead, Ph.D.
INSTITUTION: University of North Carolina, Chapel Hill, NC
GRANT NO.: 1R01DK57048-01
KEYWORDS: Biofeedback, fecal incontinence, constipation, pelvic floor dyssynergia
TYPE STUDY: Clinical
AMOUNT: $75,000
Among constipation patients, half are reported to have pelvic floor dyssynergia, a condition marked by an inability to relax pelvis floor muscles during evacuation. Biofeedback has been recommended for the treatment of both conditions because uncontrolled studies over the past 10-25 years suggest that these treatments are as effective as medical or surgical management and involve no risk. However, placebo-controlled trials are lacking in this area. The aims of the proposed research are: 1) to compare biofeedback to alternative therapies for which patients have a similar expectation of benefit; 2) to identify which patients are most likely to benefit; and 3) to assess the impact of treatment on quality of life. Two long-term, prospective, single-blind studies will be conducted. Study I will compare biofeedback for the treatment of fecal incontinence to a standard therapy, Kegel exercises. Study II will compare biofeedback for pelvic floor dyssynergia to a skeletal muscle relaxant drug (diazepam) and to placebo medication. These studies will help to establish the efficacy of biofeedback on the treatment of defecatory disorders.
TITLE: Neurotensin's Role in Models of IBS-Related Hyperalgesia NIDDK
P.I.: Robert E. Carraway, Ph.D.
INSTITUTION: University of Massachusetts, Worcester, MA
GRANT NO.: 1R01DK56999-01
KEYWORDS: Neurotensin, irritable bowel syndrome, stress responses, bowel hyperalgesia
TYPE STUDY: Basic
AMOUNT: $50,000
Neurotensin (NT), a gastrointestinal peptide, participates in modulating pain perception, mediating stress responses and regulating digestive motility/secretion. NT works closely with mast cells which coordinate neuro-endocrine immune activities in the gut. This project hypothesizes that NT-mast cell interactions are involved in physiological visceral perception and/or pathological visceral hyperalgesia. It is likely that multiple chemical mediators are involved in visceral hypersensitivity associated with stress-related functional bowel disorders. This proposal will address the potential role of neurotensin as a key mediator of the pathological hyperalgesia associated with irritable bowel syndrome using animal models of post-stress and post-inflammatory bowel hypersensitivity. The hypothesis will be tested using NT receptor antagonist, an NT-knockout mouse model, and a mast cell deficient mouse model.
TITLE: Effect of Menstrual Cycle and IBS on CNS Processing of Gut Stimuli NIDDK
P.I.: Ann Ouyang, M.D.
INSTITUTION: Milton S. Hershey Medical Center, Hershey, PA
GRANT NO.: 1R21DK57053-01
KEYWORDS: Irritable bowel syndrome, menstrual cycle, anxiety, visceral sensitivity
TYPE STUDY: Clinical
AMOUNT: $50,000
Recent evidence suggest that patients with irritable bowel syndrome (IBS) have heightened sensitivity to visceral stimuli. Little is known about factors affecting visceral sensitivity, reasons for the higher female prevalence, or the central nervous system processing of visceral sensitivity stimuli, and if this process is altered in IBS. The investigators hypothesize that: 1) menstrual cycle stage affects visceral sensitivity in both control female subjects and in subjects with IBS; 2) the areas of the brain which are activated by visceral stimulation are dependent on both the degree of distension and by the perception that the stimulus is painful; and 3) the areas of the brain activated in IBS subjects when the stimulus is painful differ from areas activated in control subjects, and that this difference may be due to the effect of anxiety. Specific aims of the study are: 1) to determine the effect of menstrual cycle on the perception of rectal balloon distention and transcutaneous nerve stimulation (TNS) in subjects without bowel symptoms (controls); 2) to determine the effect of menstrual cycle on these responses in subjects with IBS; 3) to compare the responses between controls and IBS subjects; 4) to determine the regions of the brain activated in response to rectal (non-painful and painful) and non-visceral (TNS) stimulation; and 5) to determine the influence of the state of anxiety on these parameters. An understanding of cerebral processing of non-painful and painful visceral stimuli will be helpful in defining the pathway for perceiving pain in the IBS and other functional gut disorders, and for directing therapy appropriately.
TITLE: Regional Cerebral Activation with Visceral Pain in IBS Controls NIDDK
P.I.: Howard R. Mertz, M.D.
INSTITUTION: Vanderbilt University, Nashville, TN
GRANT NO.: 1R21DK57047-01
KEYWORDS: Irritable bowel syndrome, limbic system, antidepressants
TYPE STUDY: Clinical
AMOUNT: $25,000
Recent data have demonstrated abnormal activation of limbic and paralimbic pain centers in irritable bowel syndrome (IBS) in response to rectal pain. Conversely, non-limbic pain centers including the VPL-thalamus, sensory cortex and insular systems are critical to the generation of symptoms in IBS. This project will compare the activity of the limbic system in IBS and controls in response to graded rectal distention (non-painful and painful). Activity in non-limbic pain centers and autonomic outflow centers will be compared between IBS and controls. Understanding the function of the limbic and non-limbic pain centers in healthy and disease states, and the effect of stress and medication on the pain experience may lead to improved pharmacological and behavioral therapies for visceral pain, including IBS.
TITLE: Cognitive Therapy as a Treatment for Irritable Bowel Syndrome (IBS) NIDDK
P.I.: Edward Blanchard, PhD
INSTITUTION: State University of New York, Albany, NY
GRANT NO.: 1R01DK54211-01A1
KEYWORDS: Irritable bowel syndrome, cognitive therapy
TYPE STUDY: Clinical
AMOUNT: $100,000
Recent research suggests that cognitive therapy (CT) is highly effective (70-80% clinically improved) in the short-term (3 months)as a treatment for IBS. This application seeks to replicate and extend previous small-scale studies by conducting a controlled clinical trial of CT vs. a self-help support group as an attention placebo control and follow-up of the treated patients for at least 12 months.
GENETICS
TITLE: Folate Pathway Genes and Risk for Orofacial Clefts NIDCR
P.I.: Gary M. Shaw, DrPH
INSTITUTION: March of Dimes Birth Defects Foundation, Emeryville, CA
GRANT NO.: 1R01DE12898-01A1
KEYWORDS: genetics, nutrition, risk factors, reproductive development
TYPE STUDY: Clinical
AMOUNT: $250,000
The research program will investigate nutritional and genetic risk factors for orofacial clefts. The specific aims for the 3-year studyare to assess the potential "gene-environmental" interplay between genetic variation of 3 potential folate pathway genes (folate receptor gene, reduced folate carrier, and the N-acetal transferace 1 gene) among probands, maternal folic acid/multivitamin intake, and the risk of orofacial clefts. The researchers propose to investigate the hypothesis that one or more of the 3 folate pathway genes are responsible for inadequate transport, accumulation, or metabolism of folate during critical stages of craniofacial development, making embryos susceptible to orofacial clefts even in the presence of clinically adequate maternal folate intake. By combining state-of-the-art molecular biology approaches, new genetic findings, and one of the largest case-control studies done on orofacial clefts, the investigators will determine if maternal supplemental folic acid intake overcomes folate transport or metabolic dysfunction that may occur as a result of the embryo genotypic variation for the 3 folate pathway genes and thus reduce the risk for orofacial clefting. The research design will be case-control, including approximately 1200 cases and controls, and will utilize maternal interview data in conjunction with genotyping of the folate receptor gene. As one of the first attempts at investigating environmental and molecular genetic interactions in the epidemiology of congenital anomalies, this study endeavors to enhance our general understanding of the causes of orofacial clefts as well as our specific understanding of the apparent protective effect of folate supplementation on the occurrence of clefts.
HEALTH PROMOTION
TITLE: An Exercise Intervention for Minority College-Age Women NINR
P.I.: Karen T. D'Alonzo, MSN
INSTITUTION: Rutgers, The State University of New Jersey, Piscataway, NJ
GRANT NO.: 1F31NR07538-01A1
KEYWORDS: exercise, minority, health promotion
TYPE STUDY: Clinical
AMOUNT: $25,400
This award supports the research training activities of a predoctoral student who will implement an intervention study that encourages exercise as a health promotion behavior for African American and Hispanic female college students. The specific aims of the study are to: 1) identify the perceived benefits of and barriers to initiation and maintenance of exercise among female minority college students; 2) conduct focus groups comprised of minority women in college as a basis for planning and implementing a culturally sensitive exercise intervention; 3) develop and test a culturally sensitive exercise intervention to promote physical fitness among female minority college students; and 4) develop strategies to crystallize exercise as a life long habit among minority young women. Utilizing the responses of focus groups, a culturally relevant exercise intervention for Black and Hispanic female college students will be developed and tested. The study will utilize a two-group crossover lag experimental design. Hypotheses for the study are: 1) there will be specific positive changes in selected biological and behavioral parameters in the crossover lag and experimental groups after 16 weeks of an exercise intervention; 2) there will be a significant positive correlation between self-efficacy and intention to exercise; 3) there will be a significant positive correlation between perceived benefits to exercise and continued participation in exercise activities post intervention.
TITLE: Nurse-Guided Exercise Protocol for Minority Women NINR
P.I.: Colleen S. Keller, Ph.D.
INSTITUTION: The University of Texas Science Center, San Antonio
GRANT NO.: 1R55NR04888-01A2
KEYWORDS: menopause, minority, exercise, risk factors, health promotion
TYPE STUDY: Clinical
AMOUNT: $100,000
Sedentary activity and obesity threaten the cardiovascular health of nearly one third of U.S. women. Minority women are at particular risk for obesity and tend to engage in less physical activity than their white counterparts. Nurses in community-based treatment programs recognize the importance of physical exercise in weight management, but must rely on laboratory trials and treadmill data to accurately guide recommendations of physical activity. Examinations of the dose-response effect of physical activity have demonstrated that the most significant reductions in rates of CHD are found when sedentary individuals begin to exercise. The dose-response and desirability of low intensity exercise, performed on community sidewalks or field tracks by overweight sedentary women, have not been established. The problem is to develop an exercise protocol that is of low enough intensity that the probability of minority women sustaining exercise at that level is high, yet is of sufficient intensity to be effective with respect to beneficial effects on CHD. Specific aims are to: 1) compare the effects of low and moderate intensity of exercise in Mexican American and African American women on blood lipids, fat cell size and function, LDL, particle size, body fatness and fat distribution, and exercise tolerance; 2) determine the effects of low and moderate intensity of exercise on exercise maintenance in sedentary, obese minority women; 3) explore the dose-response relationship of exercise volume, where volume is an interaction term of intensity X maintenance, to total serum cholesterol, triglycerides, HDL-C, LDL-C, body fatness, fat cell size, lipolysis, LDL particle size, and exercise endurance. Two experimental groups will be employed. Both randomized groups will walk 4 days a week, for 30 minutes a day. Group 1 will walk at 40% of target heart rate; Group 2 will walk at 65% of their target heart rate. A unique feature of this study is that it proposes an interdisciplinary approach to the understanding of the biobehavioral mechanisms underlying exercise and its relationship to fat metabolism. In addition, it will increase understanding of the process by which exercise dose (frequency) produces a graded effect on the risk factors as measured by body composition, blood lipids, and fat cell size and function?
TITLE: Exercise and Perimenopausal Symptoms: A Randomized Trial NINR
P.I.: Suling Li, Ph.D.
INSTITUTION: Loyola University of Chicago, Chicago, IL
GRANT NO.: 1R55NR04946-01A1
KEYWORDS: exercise, menopause, hormone replacement therapy, clinical trial
TYPE STUDY: Clinical
AMOUNT: $80,000
The long term goal of this study is to increase understanding of the role of exercise in promoting health in perimenopausal women. The specific aim are 1) to describe the frequency and distress of perimenopause-associated symptoms in women undergoing a 12-week individualized exercise program with a personal trainer at baseline, 12 weeks, and one year; 2) to determine the effect of a 12-week individualized exercise program with a personal trainer on the frequency and distress of perimenopause-associated symptoms in women with/without hormone replacement therapy (HRT); 3) to evaluate the synergistic effect of exercise with HRT on the frequency and distress of perimenopause-associated symptoms; 4) to characterize body composition (fat mass, lean body mass, and bone mass) in exercising/non-exercising perimenopausal women with and without HRT at baseline, 12 weeks, and one year; and 5) to determine the effect of a 12-week individualized exercise program with a personal trainer on sustain ability of exercise participation at one year follow-up. Within the context of a randomized block controlled clinical trial, a total of 160 perimenopausal women, aged 40-55 years, will be studied. Previously sedentary women with HRT (n-80) and without HRT (n=80) will be randomly assigned to one of the two conditions: exercise and non-exercise. Thus, four groups (exercise with HRT; exercise without HRT; non-exercise with HRT; non-exercise without HRT) will be formed. The exercise intervention will be a 12-week facility-based individualized exercise program with a personal trainer. The outcome measures include 1) perimenopause-associated symptoms (vasomotor, menstrual, psychosomatic and sexual); 2) body composition (fat mass, lean body mass, and bone mass); and 3) sustain ability of exercise participation. Measurements will be taken at baseline, 12 weeks, and one year. The proposed study will fill an existing gap by examining whether exercise will relieve perimenopause-associated symptoms and/or enhance the effect of HRT in relief of perimenopause-associated symptoms. Findings will provide much needed information for prescription of exercise aimed at the management of perimenopause-associated symptoms.
IMMUNITY/AUTOIMMUNITY
TITLE: Registry and Repository of African Americans with Rheumatoid Arthritis NIAMS
P.I.: Larry Moreland, M.D.
INSTITUTION: University of Alabama at Birmingham, Birmingham, AL
GRANT NO.: 1N01AR02247
KEYWORDS: African American, disease registry, rheumatoid arthritis
TYPE STUDY: Clinical
AMOUNT: $200,000
This 5-year project will be housed at the University of Alabama at Birmingham. It will establish a Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis registry which serves to identify genetic and non-genetic prognostic factors of disease outcome using radiographic presence of bony erosions as the primary outcome measure (at 3 years disease duration). The registry will serve as the basis for prospective analyses of factors predictive of the clinical phenotype and outcomes. Four major academic medical centers in the southeast U.S. will gather data which will provide a resource for investigators interested in the genetics of RA in AA. The CLEAR registry will be utilized to examine the hypothesis that HLA-DR alleles and cytokine polymorphism in the tumor necrosis factor- alpha [TNF-alpha]/lymphotoxin (LT)- alpha, interleukin-1 (IL-1), and IL-6 loci, predict the presence or absence of erosion on hand and feet radiographs at 3 years disease duration in AA. The principal investigator, Dr. Larry Moreland, is a clinical researcher whose primary research interest has been the evaluation of biologic response modifiers (and their mechanisms) which are targeted at the disease process in rheumatoid arthritis.
TITLE: T-Cell Reconstitution After Stem Cell Autograft NIAID
P.I.: Jan Storek, MD, PhD
INSTITUTION: Fred Hutchinson Cancer Research Center, Seattle, WA
GRANT NO.: R01A146108-01
KEYWORDS: T cells
TYPE STUDY: Clinical
AMOUNT: $60,000
The goal is to evaluate how the T cell repertoire is reestablished in patients with autoimmune diseases who have undergone lymphocytopenia from high dose chemotherapy/radiation plus anti-thymocyte globulin followed by reconstitution with autologous transplantation of hemopoietic (CD34+) precursors. The hypothesis is that in young individuals, a substantial number of regenerating T cells originate from hemopoietic progenitors whereas in older individuals, the vast majority of T cells originate from the expansion of preexisting T cells. The techniques used will be spectratyping, sequencing of the T cell receptor genes withing a single spectratyping band and quantifying T cells that contain T cell receptor-rearrangement circles.
TITLE: Mechanism of Copaxone Therapy in MS NIAID
P.I.: Michael Racke, M.D.
INSTITUTION: UT Southwestern Medical Center at Dallas, TX
GRANT NO.: 1R01A147133-01
KEYWORDS: Multiple sclerosis, MS, Copaxone
TYPE STUDY: Clinical
AMOUNT: $140,000
Multiple Sclerosis (MS) patients are categorized on the basis of whether they have clearly defined relapses, relapsing-remitting MS (RRMS), or whether they are progressing. Progressing patients are further divided on the basis of whether they initially experienced relapses (secondary progressive MS), or whether they deteriorate slowly without evidence of relapses or remissions (primary progressive MS). One question is whether the patients with primary progressive MS (PPMS) differ from the patients with secondary progressive MS or whether they represent different aspects of a clinical pathologic spectrum. This group has shown that patients with RRMS have myelin-reactive T cells that are less dependent upon costimulation than myelin-reactive T cells from normal controls. The goal is to test the hypothesis that myelin-reactive T cells in patients with PPMS can be distinguished from naive myelin-reactive T cells by a lack of dependence upon costimulation for activation and that costimulatory requirements for these myelin-reactive T cells change during the course of disease. Glatiramer acetate (Cop-1, Copaxone) has previously been shown to reduce the number of relapses in RRMS and is now being tested for efficacy in patients with PPMS. It is unclear how Copaxone exerts its therapeutic effect. This study will determine whether Glatiramer alters cytokine secretions of myelin-reactive T cells and the T cell repertoire in PPMS.
TITLE: Denver Autoimmunity Center of Excellence NIAID
P.I.: Brian L. Kotzin, M.D.
INSTITUTION: University of Colorado Health Sciences Center, Denver, CO
GRANT NO.: 1U19AI46374-01
KEYWORDS: Type 1 diabetes, lupus nephritis, rheumatoid arthritis
TYPE STUDY: Clinical and basic
AMOUNT: $75,000
A Center of Excellence for Autoimmunity will be established at the University of Colorado Health Sciences Center. The Center builds on a strong research and clinical base in Type 1 diabetes, celiac disease, systemic lupus, rheumatoid arthritis, multiple sclerosis, autoimmune skin disease, autoimmune pulmonary disease and other autoimmune disorders. Under this initiative, two clinical trials will be conducted. Clinical Project 1 will evaluate subcutaneous insulin vaccination to prevent the appearance anit-islet autoantibodies in infants at high risk for the development of autoantibodies and disease. Clinical Project 2 will test humanized anti-C5 mAbs in patients with active lupus nephritis. Three basic components will be studied: 1) to define the T-cell specificities and distribution of insulin-and islet antigen-reactive T-cells in murine models and patients with Type 1 diabetes; 2) to determine the effects of inhibition of IL-18 and complement on cytokine production and disease in collagen-induced arthritis and rheumatoid synovion; and 3) to define the non-MHC genetic contributions to different clinical subtypes of autoimmune polyendocrine syndrome II. These basic projects will provide important information to design future clinical trials, to monitor the effectiveness of immunologic therapies, and/or provide surrogate markers to correlate with immunologic therapies in autoimmune diseases.
TITLE: Penn Autoimmunity Center of Excellence NIAID
P.I.: A.M. Rostami, M.D., Ph.D.
INSTITUTION: University of Pennsylvania, Pennsylvania, PA
GRANT NO.: 1U19AI146358
KEYWORDS: Multiple sclerosis, systemic lupus erythematosis, interleukin-12
TYPE STUDY: Clinical and basic
AMOUNT: $75,000
A Center of Excellence for Autoimmunity at the University of Pennsylvania School of Medicine will be established. It will consist of four projects (three clinical and one basic) and two cores. The clinical component of the Center consists of three clinical trials: 1) a Phase I/II trial on the use of antibody to interleukin-12 for the treatment of multiple sclerosis; 2) a Phase I/II trial on the use of interleukin-12 in the treatment of inflammatory bowel disease; and 3) the use of anti-CD20 antibody for the treatment of systemic lupus erythematosus. The basic science component is focused on the elucidation of the basic mechanisms of autoimmunity and immuno-modulation related to the clinical trials. Investigators will study the role of IL-12 in the pathogenesis and therapy of multiple sclerosis and its animal counterpart, experimental autoimmune encephalomyelitis. Also, they will focus on the mechanisms of anti-B-cell therapy in systemic lupus erythematosus and its murine model. An immunology core and an administrative core will be supported under this initiative.
TITLE: Autoimmunity Center of Excellence NIAID
P.I.: Leonard Chess, M.D.
INSTITUTION: Columbia University College of Physicians & Surgeons, New York, NY
GRANT NO.: 1U19AI46132
KEYWORDS: Multiple sclerosis, Type 1 diabetes, scleroderma, SLE
TYPE STUDY: Clinical
AMOUNT: $75,000
This Center will establish an interdisciplinary basic and clinical research program to focus on the evaluation of novel therapeutic approaches to five autoimmune diseases: rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, and scleroderma. The investigators hypothesize that there are four principal events involved in the immunopathogenesis of these diseases: 1) predisposing genes establish a T-cell repertoire capable of recognizing self peptides intrinsic to the autoimmune process; 2) previously tolerant autoreactive CD4+ T-cell clones become activated and expand to change the T-cell repertoire to reflect autoreactive effector T-cells; 3) regulatory mechanisms, including the activation of TH1 and TH2 CD4+ T-cell subsets as well as those involving CD8 T-Cells fail, through processes such as clonal deletion or changes in the cytokine milieu; and 4)pathogenic autoantibodies develop through cognitive T-cell B-cell interactions which effect tissue injury. In these diseases one would predict that reducing the clonal expansion of relevant autoreactive T-cell by blockade of T-cell receptor signaling or interruption of the CD40 ligand-dependent pathway could down modulate disease activity. Also, interruption of the inflammatory effector functions of T-cell mediated by TNF or CD40L would similarly reduce disease potential. These hypotheses will be tested during the natural history of disease and during specific immune interventions.
TITLE: Autoimmunity: Treatment by Co-stimulatory Signal Blockade NIAID
P.I.: Samia J. Khoury, M.D.
INSTITUTION: Brigham and Women's Hospital, Boston, MA
GRANT NO.: 1U19AI46130
KEYWORDS: Multiple sclerosis, inflammatory bowel disease, psoriasis
TYPE STUDY: Clinical
AMOUNT: $75,000
A Center of Excellence for Autoimmunity will be established at the Brigham and Women's Hospital. Projects supported under this initiative will focus on the study of therapy of autoimmune diseases by blocking co-stimulatory signals. Investigators will focus on the CD40-CD40L pathway. The human diseases of major focus are multiple sclerosis, inflammatory bowel disease, and psoriasis. All are organ specific diseases where T-cells appear to be essential in initiating the immune response and lead to the particular disease pathology. Four projects are supported. The overall goals of project 1 are to study in a pilot trial the efficacy and safety of anti-CD40L therapy in multiple sclerosis. The goals of project 2 are to study in a pilot trial the efficacy and safety of anti-CD40L therapy in inflammatory bowel disease. Project 3 will focus on the immunologic changes associated with anti-CD40L therapy in patients with multiple sclerosis and inflammatory bowel disease. Project 4 will study the immune mechanisms of psoriasis. Data obtained from the pilot studies will be useful in designing Phase m clinical trials, and immunologic investigations will help to identify surrogate markers for disease activity.
TITLE: New Immunotherapies for Autoimmune Disease NIAID
P.I.: R.P. Eaton, M.D.
INSTITUTION: University of New Mexico, Albuquerque, NM
GRANT NO.: T15AI07586
KEYWORDS: ethics training
TYPE STUDY: training
AMOUNT: $80,000
The primary expectation of this initiative is to develop, refine, and evaluate an annual program that would serve to increase the ethical acceptability of human investigation on the part of faculty, staff, and medical students at a large university medical center. Survey instruments, questionnaires, and focused interviews will be conducted to critically access the strengths, weaknesses, and impact of the research ethics course.
TITLE: Immune Mechanisms of Anti-CD40L Trial in Systemic Lupus Erythematosis NIAMS
P.I.: Syamal Datta, MD
INSTITUTION: Northwestern University, Evanston, IL
GRANT NO.: 1R01AR46309
KEYWORDS: Lupus, anti-CD40L
TYPE STUDY: Clinical
AMOUNT: $50,000
CD40L is hyper-expressed by lupus B cells for abnormally prolonged periods, thus sustaining the production of pathogenic autoantibodies. A brief therapy of three injections of anti-CD40L in one week into lupus mice prevents the development of nephritis for more than a year. This clinical trial provides an opportunity to study the effects of anti-CD40L on the human immune system in vivo, particularly on the cells participating in the chronic ongoing autoimmune response in lupus patients. This study will examine the status of autoimmune T and B cells that are involved in the production of pathogenic anti-nuclear autoantibodies, before, during, and after therapy .
TITLE: Combining of N-of-1 Trials to Assess Fibromyalgia Therapies NIAMS
P.I.: Deborah R. Zucker, M.D.
INSTITUTION: New England Medical Center, Boston, MA
GRANT NO.: R01AR45416
KEYWORDS: Fibromyalgia, amitriptyline, fluoxetine
TYPE STUDY: Clinical
AMOUNT: $140,000
Fibromyalgia is a common rheumatologic condition and treatment is a challenge. A recent study reported that combination therapy of amitriptyline and fluoxetine resulted in significantly greater improvement in patients' symptoms as compared with either drug alone. This project will use patient focused N-of-1 trials and combines these trials' results to obtain population estimates of treatment effectiveness. This will extend into community practice to enable comparison of center-based and practice-based results. This will also provide a methodological tool to obtain data from community physicians in practice-based settings.
TITLE: Mechanisms of Lupus Induction in L-Canavanine NIEHSThe sex difference in estrogen exposure may explain the sex imbalance in Systemic Lupus Erythematosus (SLE) risk. The specific aims of this proposal are to: 1) Determine androgen receptor (AR), estrogen receptor (ER), and cytochrome P450 genotypes in SLE subjects and controls by polymerase chain reaction based methodologies in a large SLE case/control study; and 2) Determine the relative importance of genetic markers in aim one with endogenous and exogenous estrogens and with exposure to organochlorines in predicting risk of SLE.
TITLE: Novel Proteins Associated with SS-A/Ro in Target Organs NIAID
P.I.: Edward K. Chan, Ph.D.
INSTITUTION: The Scripps Research Institute, LaJolla, CA
GRANT NO.: 1R21AI47859-01
KEYWORDS: Autoimmune disease, systemic lupus erythematosus, neonatal lupus
TYPE STUDY: Basic
AMOUNT: $100,000
Anti-SS-A/Ro antibodies are important clinical serological markers for systemic lupus erythematosus, Sjogren syndrome and sub-acute cutaneous lupus, which predominantly affect women of working age and during their childbearing year. They are of importance in neonatal lupus erythematosus {NLE}, a disease of infants born to women with lupus. Two cellular proteins, 60 and 52kDa, have been identified as the predominant targets of the autoimmune response. These antibodies are nearly universal in the sera of mothers whose children have cutaneous and cardiac manifestations of neonatal lupus and they have been eluted from affected fetal hearts. The investigator has identified a novel 75kDa phosphoprotein (pp75) that serves as an interaction partner for the 60kDa SS-A/Ro protein, and is an autoantigen recognized by antibodies in sera from patients with Sjogren syndrome and mothers of children with NLE. This research will further confirm the interaction between SS-A/Ro and this binding protein. It will explore the association of SS-A/Ro antigens with other tissue-specific and ubiquitously expressed proteins in the skin, heart, and salivary glands using yeast two-hybrid screen with respective cDNA libraries. Differences and similarities among interactions defined in the three affected organs should be highly informative. The results of these studies will have important implications for the prevention and treatment of these autoimmune diseases, in particular neonatal lupus.
TITLE: Mechanisms of Anti-DNA Production in Autoimmune Mice NIAID
P.I.: David S. Pisetsky, M.D., Ph.D.
INSTITUTION: VA Medical Center, Durham, NC
GRANT NO.: 1R21AI44808-01A1
KEYWORDS: autoimmune diseases, systemic lupus erythematosus
TYPE STUDY: Basic
AMOUNT: $204,275
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the production of antibodies to DNA (anti-DNA). These antibodies serve as markers of diagnostic and prognostic significance. As a model to elucidate the mechanism of this response, the investigator has studied the effects of immunization of normal and autoimmune mice with bacterial DNA. This DNA is a potent immunogen because of its content of CpG motifs that stimulate B cell activation and cytokine production. In normal mice, bacterial DNA can induce antibodies specific for the immunizing DNA while in autoimmune NZB/NZW mice, immunization leads to the production of autoantibodies with properties of SLE anti-DNA. Immunized NZB/NZW mice, however, fail to develop renal disease, possibly related to cytokine effects. To analyze further this model, three specific aims are proposed: 1) to investigate the genetic basis of induced anti-DNA production through study of a variety of inbred and congenic strains immunized with bacterial DNA; 2) to investigate the ability of mammalian DNA to inhibit immune responses elicited by bacterial DNA and other immune stimulants; and 3) to assess mechanisms by which bacterial DNA can stimulate cellular responses, focusing on the basis of DNA binding and uptake. The responses of mice deficient in the Type A macrophage scavenger receptor, a putative DNA receptor, will be assessed. Together, these studies will clarify important steps by which foreign DNA antigen can modulate the course of autoimmunity.
TITLE: Post Translational Modifications and Autoimmunity NIAID
P.I.: Mark J. Mamula, Ph.D.
INSTITUTION: Yale University, New Haven, CT
GRANT NO.: 1R21AI48120-01
KEYWORDS: autoimmune disease, systemic lupus erythematosus
TYPE STUDY: Basic
AMOUNT: $100,000
A principle purpose of the immune system is to protect the host from infectious pathogenic microorganisms. Lymphocytes have been programmed to differentiate self tissue antigens from foreign antigen. However, the appearance of autoimmune diseases and the presence of autoreactive lymphocytes in the normal population illustrates that the regulation of immunity is far from perfect. Systemic autoimmune diseases are the product of a complex interaction of lymphocytes, soluble macromolecules, and self tissues leading to the pathology of disease. Autoimmune responses often target multiple determinants within an autoantigen. For example, in systemic lupus erythematosus (SLE), autoantibodies are directed at a number of determinants on small nuclear ribonucleoproteins (snRNPs) and on nucleosomes. The self or foreign proteins involved in the spontaneous initiation of these autoimmune responses is not known. The investigator has recently identified the ability of a novel post-translational protein modification, termed isoaspartyl, to confer autoimmunity to otherwise immunologically inert self peptides. For example, the immunization with isoaspartyl forms of snRNPs can provoke autoantibody responses typical of human SLE. Isoaspartyl peptide modifications arise frequently in aged and stressed cells. Research conducted under this project will: 1) examine the presence of isoaspartyl forms of lupus autoantigens in resting, aged, and activated lymphocyte populations and determine their ability to circumvent immune tolerance; 2) examine the immunologic abnormalities, lymphokine responses and intracellular signaling, in murine models unable to repair isoaspartyl modifications (PIMT knockout mice); and 3) study the progression of spontaneous lupus autoimmunity and pathology in MRL lpr/lpr-PIMT-/- mice, a murine model of human SLE. This proposal will define the biological and immunological implications of post-translational protein modifications. Overall, the studies will address mechanisms important in the induction and perpetuation of autoimmune disease. A more thorough understanding of the earliest events in the genesis of autoimmunity may help identify important elements to exploit for the immunologic intervention of these diseases.
TITLE: Differentiation and Migratory Fate of Moncyte-Derived Cells NIAID
P.I.: Gwendalyn J. Randolph, Ph.D.
INSTITUTION: Weill Medical College of Cornell University, New York, NY
GRANT NO.: 1R01AI49653-01
KEYWORDS: monocyte differentiation, atherosclerosis
TYPE STUDY: Basic
AMOUNT: $254,250
During resolution of inflammation, some monocytes migrate to lymph nodes that drain the periphery. However, few macrophages are found in lymph, in contrast to the presence of abundant veiled cells of the dendritic cell system of antigen-presenting cells. Recent research indicates that monocyte-derived cells that migrate into lymph in vivo are predominantly those that simultaneously differentiate into dendritic cells. Migration into lymphatic vessels entails crossing lymphatic endothelium in the ablumenal-to-lumenal direction (reverse transmigration). Reverse transmigration has been described in atherosclerosis and may represent a means by which atherosclerotic lesions can regress. In an in vitro model in which human endothelial cells are grown on collagen, half of human monocytes that initially migrate across endothelium to enter the underlying collagenous matrix exit the cultures by reverse transmigration. Reverse-transmigrated monocytes differentiate into dendritic cells. In contrast, monocyte-derived cells that remain in the subendothelium become macrophages. The investigator will 1) test whether differentiation of monocyte-derived cells and their migration from tissues are mechanistically linked and will study the molecules and cellular interactions that promote the development of monocytes to dendritic cells in the context of an endothelial environment; 2) address whether conditions that favor dendritic cell development from monocytes will increase reverse transmigration or whether only a subset of monocytes have the capacity to become dendritic cells. Antagonism of the human transmembrance transporter p-glycoprotein (MDR-1) inhibits reverse transmigration of monocyte-derived cells and lymphatic migration of skin dendritic cells. A related transporter, multidrug resistance related protein (MRP), is also required for the migration of mouse dendritic cells to draining lymph nodes. He will also 3) pursue the mechanism by which these transporters regulate migration of dendritic cells and determine whether they act by affecting differentiation. Understanding the mechanisms that regulate the differentiation of monocytes into dendritic cells and their subsequent trafficking to lymph nodes may reveal approaches for enhancing immune responses in situ and for reducing macrophage accumulation in chronic inflammatory diseases, such as atherosclerosis.
TITLE: Lupus Nephritis: Role of Environment and Occupational Exposure NIAMS
P.I.: Mary A. Dooley, M.D.
INSTITUTION: University of North Carolina, Chapel Hill, NC
GRANT NO.: 1R55AR46943-01
KEYWORDS: autoimmune, systemic lupus erythematosus, blacks, white
TYPE STUDY: Clinical
AMOUNT: $99,999
The purpose of the epidemiologic study is to evaluate the potential role of environmental chemicals in the development of lupus nephritis, and to elucidate how these exposures might influence the racial and gender disparity seen in this disease. The incidence of lupus in American blacks is much higher than in whites, develops at an earlier age, and has increased morbidity and mortality. Significant renal involvement occurs in up to 40% of patients and is more frequent and more rapidly progressive in blacks. Renal manifestations of systemic lupus erythematosus (SLE) are highly variable in clinical presentation and prognosis, ranging from mild asymptomatic proteinuria to rapidly progressive glomerulonephritis leading to endstage renal disease (ESRD). This clinical heterogeneity is accompanied by diverse histologic abnormalities in renal biopsy specimens. SLE is characterized by a striking female predominance. American Blacks are disproportionately affected by SLE with earlier age at onset and more frequent renal involvement. Progression of lupus nephritis to ESRD occurs more rapidly and more frequently in this population. No clinical, laboratory or histopathologic factors clearly identify black patients predisposed to more aggressive treatment-resistant lupus nephritis. Environmental factors have been evaluated as potentially important in the development of SLE and renal disease and may play an important role in patients with SLE who develop renal involvement. Previous studies have examined the role of socioeconomic status measures, serologic markers and MHC genes as explanations for the observed racial differences, but no study to date has examined occupational and environmental risk factors in this context. Exposure to agents such as silica dust, heavy metals, hydrocarbons, smoking or hormonal factors may influence the development, progression or severity of lupus nephritis. Study subjects will be taken from the Glomerular Disease Collaborative Network and the Carolina Lupus Study. Control patients with lupus without renal disease and normal controls from the Carolina Lupus (CLu) study, a population-based, case control study nearing completion in 60 counties in North and South Carolina evaluating environmental, hormonal and genetic risk factors for the development of SLE, will be included.
TITLE: Heart Disease in Rheumatoid Arthritis NIAMS
P.I.: Sherine E. Gabriel, M,D., M.Sc.
INSTITUTION: Mayo Foundation, Rochester, MN
GRANT NO.: 1R01AR46849-01
KEYWORDS: autoimmune, cardiovascular, risk factors
TYPE STUDY: Clinical
AMOUNT: $175,000
The hypotheses to be tested in this proposal are built on findings from two disparate lines of investigation. The first is the recent data suggesting that the excess mortality experienced by people with rheumatic arthritis (RA) may result from increased rates of coronary heart disease (CHD) among RA patients compared to the general population. The second is the rapidly growing body of evidence indicating that chronic systemic inflammation (such as that which occurs in RA) plays an important role in the pathogenesis of CHD. As the most common chronic systemic inflammatory disease, RA may represent an ideal model to study the role of chronic inflammation in CHD. Three specific aims are proposed to investigate this subject: 1) using a cohort study, the investigator will test the hypothesis that the incidence of acute MI (the central manifestation of CHD) is higher in RA subjects compared to controls; 2) identifying high-risk RA subgroups and using a novel adaptation of the case-cohort design to investigate the interactions between RA and the major CHD risk factors (e.g., smoking, hyperlipidemia, exogenous estrogens); and 3) to conduct studies on archived autopsy heart tissue to test the hypothesis that coronary atherosclerosis is more extensive in RA subjects compared to matched controls. These results will lay the foundation for a program of research aimed at elucidating the mechanisms for CHD and RA patients and at improving the understanding of the role of inflammation in the pathogenesis of CHD in the general population.
TITLE: B Cell Hyperactivity in Autoimmunity NIAMS
P.I.: Ann Marshak-Rothstein, Ph.D.
INSTITUTION: Boston University , Boston, MA
GRANT NO.: 3R01AR35230-13S1
KEYWORDS: autoimmune, rheumatoid arthritis
TYPE STUDY: Basic
AMOUNT: $99,999
Rheumatoid factors (RF) were first identified in the 1940's as autoantibodies reactive with autologous Ig present in the synovial fluid of patients with rheumatoid arthritis. High levels of RF-containing immune complexes and/or cryoglobulins have also been found in patients with microbial infections such as infectious endocarditis, in individuals presenting with hepatitis C-related essential mixed cryogloblulinemia, and in Fas/FasL-deficient (lpr/gld) mice. These immune complexes can deposit in blood vessel walls, form complement, and thereby promote the vasculitis and glomerulonephritis associated with these diseases. Thus the contribution of RF to the effector arm of systemic autoimmune disease is well documented. Nevertheless, exactly how RF+ B cells become activated, why RF so frequently present as monoclonal gammopathies, and what role RF+ B cells might play in the initiation and propagation of the autoimmune cascade are questions that remain unresolved. This study will address these questions by using an RF+ B cell receptor transgenic mouse line, developed from a prototypic M.R.L./lpr-derived autoantibody, to evaluate the role RF+ B cells might play in the presentation of autoantigens. Specifically, the project will be organized to: (1)determine the ability of monomeric IgG2a and different types of IgG2a-containing immune complexes to activate RF+ B cells and evaluate the ability of activated and non-activated RF+ B cells to process and present autoantigenic epitopes; (2)evaluate the ability of RF+ B cells to stimulate autoreactive T cells in vitro and to determine the specificity of the RF-activated ART; and (3)assess the ability of RF+ B cells and/or RF-activated ART to trigger and propagate systemic autoimmune disease. While dealing with RF in particular, the results of these experiments should be applicable to a more general understanding of the principles governing self/nonself recognition and tolerance induction. Moreover, this experimental strategy should also have direct relevance to human clinical syndromes associated with excessive RF production.
TITLE: Gene Therapy for Autoimmune Arthritis NIAMS
P.I.: Sherry L. Thornton, Ph.D.
INSTITUTION: Children's Hospital Research Foundation, Cincinnati, OH
GRANT NO.: 1F32AR47712-01
KEYWORDS: autoimmune, rheumatoid arthritis, gene therapy
TYPE STUDY: Basic
AMOUNT: $16,680
Gene therapy provides a possible means to deliver anti-inflammatory biological agents, such as interleukin-10, for long-term treatment of autoimmune arthritis. Adenoviral vector mediated gene therapy allows for high expression of these therapeutic proteins. However, this expression is normally short-lived, in part due to immunogenicity of the viral vector and/or transgenic protein being expressed. Studies outlined in the first two specific aims will determine whether transgene expression can be prolonged utilizing adenoviral vectors engineered to reduce immunogenicity to the adenoviral vector and/or transgenic protein product. The third specific aim functionally tests these vectors in the CIA mouse model system for their effects on autoimmune arthritis. The studies outlined in this proposal will provide valuable data in furthering the development of gene therapy for autoimmune arthritis.
INFECTIOUS DISEASES/STD
TITLE: Mid-America Adolescent STD Cooperative Research Center NIAID
P.I.: Donald Orr, M.D.
INSTITUTION: Riley Hospital, Indianapolis, IN
GRANT NO.: 1U19AI43924 01
KEYWORDS: Infectious diseases, sexually transmitted diseases, STD, multi-disciplinary, prevention
TYPE STUDY: Clinical
AMOUNT: $50,000
Sexually transmitted diseases (STD) produce very serious outcomes in women, regardless of race, and often affect their infants as well. In addressing the racial health disparities in the occurrence of STD, NIAID supports Sexually Transmitted Diseases Cooperative Research Centers (STDCRCs), which provide a multi-disciplinary approach to research in the area of STD by bringing together basic science, clinical and epidemiological research, and behavioral intervention strategies for the prevention and control of STD.
TITLE: The Viscoelasticity and Protein Compositions of the Cervix NICHD
P.I.: Chi H. Lee, Ph.D.
INSTITUTION: Northeast Louisiana University, Monroe, LA
GRANT NO.: 1R15HD40784-01
KEYWORDS: cervical mucus, spermicide/microbicides, sexually-transmitted diseases, AIDS, contraceptive development
TYPE STUDY: Basic
AMOUNT: $25,700
This study will investigate the mechanism of EDTA induced viscoelasticity changes in the cervical mucus and characterize the nature of EDTA extractable proteins. To obtain an understanding of the fundamental basis of altered mucus receptivity to sperm, it is important to define the physical and biochemical changes associated with mucus upon exposure to exogenous compounds such as Nonoxynol-9 (N-9) and EDTA, which usually reflect alterations in the macromolecular composition and its concentration.
The quantity and quality of the cervical mucus, a critical component in controlling sperm access to the upper reproductive tract, are regulated by various factors including calcium related proteins. These variations are indicated by changes in pH, viscoelastic properties, and water and protein content of cervical mucus. The removal of calcium and the consequent change in the viscosity of the cervical mucus are hypothesized as the major factors which cause an inhibitory action of the chelating agent on sperm motility in the cervical mucus. It is also hypothesized that there are EDTA extractable proteins in the cervical mucosa which are involved in sperm regulation and removal of these proteins further affect mucus receptivity to sperm. The results of this study can serve as a basis for the development of an efficient system used for protection against sexually transmitted diseases (STD)including AIDS and for a contraceptive device by regulating the physical and biochemical changes associated with cervical mucus.
TITLE: In Vitro Model of Human Vaginal Epithelium NICHD
P.I.: Ann Stapleton, M.D.
INSTITUTION: University of Washington, Seattle, WA
GRANT NO.: 1R03HD39365-01
KEYWORDS: vagina, topical microbicides, sexually-transmitted diseases, contraceptive methods
TYPE STUDY: Basic
AMOUNT: $100,000
A healthy vaginal ecosystem is critical to reproductive health. The human vaginal epithelium anatomically locationed between the external environment and protected sites in the upper genital tract, forms a barrier to infecting pathogens. Estrogen replacement therapy and many contraceptive products and devices are vaginally delivered and may affect this epithelium. Despite the importance of the vaginal epithelium in reproductive health and disease, vaginal physiology and factors affecting differentiation of the vaginal epithelium are infrequently studied, and in vitro models of this tissue have not been widely developed. The goal of this proposal is to develop a promising model for basic investigators of epithelial differentiation and susceptibility to bacterial infection, before and after in vitro exposure to hormonal and vaginal products. The investigator hypothesizes that differentiation of vaginal epithelium affects its susceptibility to infection and its response to the application of exogenous hormones and contraceptive products. Several aims will be pursued: 1) characterization of the primary vaginal epithelial cells (VECs) grown in culture for expression of differentiation markers such as keratins, epithelial differentiation markers extensively studies in related epithelia, and selected GSLs known to be involved in bacterial adherence; 2) investigation of exogenous estrogen will be applied to VEC grown in culture and parameters of epithelial differentiation, such as the expression of keratins and of GSLs; 3) studies of the adherence of Lactobacilli and of bacterial pathogens such as E. coli, which may relate to risk of premature birth, will be expanded to include the relationship between expression of differentiation markers and the effect of exogenous estrogen on susceptibility to bacterial attachment. Establishing this model will open opportunities for studying numerous aspects of women urogenital health, including testing vaginal products, probiotics, and contraceptive; understanding protective roles of organisms in the normal flora; and studying the cellular effects of hormone replacement therapy on a key target tissue, the vagina.
MENOPAUSE
TITLE: Medicine or Surgery AHRQ
P.I.: Stephen B. Hulley, M.D.
INSTITUTION: University of California San Francisco, San Francisco, CA
GRANT NO.: 5U01HS09478-03
KEYWORDS: hormone therapy, human therapy evaluation, hysterectomy, menstrual cycle disorder, uterus disorder
TYPE STUDY: Clinical
AMOUNT: $100,000
The study is a randomized clinical trial comparing the effects of enhanced medical therapy versus hysterectomy on functioning and well-being in premenopausal women with abnormal uterine bleeding who do not respond adequately after three months of initial medical management. A second randomized trial is comparing the effects of supracervical versus total hysterectomy on function and well-being in women who undergo abdominal hysterectomy. Group differences in quality-of-life, clinical, sexual function, and economic outcomes will be examined. There are four clinical centers involved with about 3000 premenopausal women over age 30 who suffer from abnormal uterine bleeding.
TITLE:Study of Women's Health Across Nation II: (SWAN II) NIA
P.I.: Dr. Sonai McKinlay, Coordinating Center, Multiple sites and investigators plus a lab
INSTITUTIONS: New England Research Institute, Watertown, MA
GRANT NO.: 2UO1AG12553-06
KEYWORDS: Menopause, aging, hormones, minorities, risk factors, disease
TYPE STUDY: Clinical
AMOUNT: $250,000
SWAN consists of both cross sectional and longitudinal studies on the natural history of menopause and a characterization of endocrinology/physiology of premenopause. Five ethnic groups are included - Caucasian, African American, Hispanic, Chinese, and Japanese. There are 7 sites across the country - Boston, Pittsburgh, Chicago, Michigan, UCLA, UC Davis and New Jersey. For the cross-sectional study, there are approximately 16,000 women enrolled ranging in age from 40-55 years to determine the age of menopause. The longitudinal study has approximately 3150 women (450 at each site) between the ages of 42-52 to determine menopause-specific physiological changes and their predictors and the impact of menopause on subsequent disease. Measurements are being made of the major reproductive axis hormones (LH, FSH, estradiol, progesterone, and testosterone), adrenal markers of aging (DHEAs), other endocrine markers (TSH, sex hormone binding globulin [SHBG]) and new ovarian markers which have the potential to define the menopausal transition and the postmenopause.
TITLE: Menopausal Depression: Chronobiologic Basis NIMH
P.I.: Barbara L. Parry, M.D.
INSTITUTION: University of California, San Diego, La Jolla, CA
GRANT NO.: 1R01MH59919-01a1
KEYWORDS: depression, menopause, hormone replacement therapy
TYPE STUDY: Clinical
AMOUNT: $100,000
The specific focus of this project will be to examine the effects of estradiol and progesterone administration on circadian rhythms in humans. The subjects will be healthy postmenopausal women. The investigators will test the hypothesis that estrogen advances the phase and enhances the amplitude and synchrony (the stability of timing relationships) of biological rhythms as measured by melatonin, sleep and activity, whereas progesterone antagonizes these effects. This proposal represents an extension of the investigators' previous work that examined the effects of endogenous changes in estradiol and progesterone during the menstrual cycle on measures of mood and circadian rhythmicity. This work led to the development of new hypotheses and treatment strategies. The current proposal will allow investigation of these hypotheses further but in a more controlled design. The investigators anticipate gaining important information on possible mechanisms mediating the effects of reproductive hormones on mood and behavior and deriving relevant clinical treatment guidelines for menopausal women.
TITLE: Botanical Dietary Supplements for Women's Health ODS
P.I.: Norman Farnesworth, Ph.D.
INSTITUTION: University of Illinois at Chicago, IL
GRANT NO.: 1P50AT00155-01
KEYWORDS: Botanicals, menopause, black cohosh, red clover
TYPE STUDY: Clinical and basic
AMOUNT: $100,000
This multi-disciplinary team of investigators will focus on the study of the safety and efficacy of botanicals used to treat women for menopause. Studies will address mechanisms of action, identification of active compounds, and characterization of metabolism, bioavailability and pharmacokinetics of active species in these botanicals. The research component will consist of the following: 1)A pharmacognosy project to carry out standardization of botanical dietary supplements and structure elucidation of active compounds; 2) Isolate active compounds for structure elucidation, and then to determine the mechanism(s) of action of botanicals; 3) Study the metabolism, absorption and toxicity of active compounds in botanicals including immunotoxicity; and 4) Carry out phase I and II clinical trials of black cohosh (Cimicifugai racemosa) and red clover (Trifolium pratense).
TITLE: Biobehavioral Health in Diverse Midlife Women NINR
P.I.: Kathryn A. Lee, Ph.D.
INSTITUTION: University of California, San Francisco
GRANT NO.: 3R01NR04259-05S1
KEYWORDS: menopause, minority, behavioral
TYPE STUDY: Clinical
AMOUNT: $100,000
This is a continuation of a longitudinal research study of midlife women ages 40-48 years at recruitment from community centers who have undergone baseline data collection beginning prior to menopause and continuing every three months. The Aims of the study are: 1) to describe the bio-psycho-social-cultural environment of midlife women (African American, Mexican/Central American, and European Americans) and change over time in biological factors(FSH, menstrual cycles, hemoglobin, body fat, and sleep), psycho-social factors(socioeconomics, family, relationship satisfaction, stress perception, symptom distress, and social support), and ethnic/cultural factors (attitudes toward menopause and aging; meanings and expectations of midlife); 2) to compare these factors for women with severe perimenopausal symptoms to women without severe symptoms; and 3) to explore symptom responses, health service, use, and health-seeking behaviors. Funding will support activities related to completion of data collection and statistical analysis of women who transition into peri- and postmenopausal midlife periods.
MENTAL HEALTH
TITLE: Black Rural and Urban Caregivers Mental Health Functioning NIA
P.I.: Lethia Chadia, Ph.D.
INSTITUTION: Washington University, St Louis, MO
GRANT NO.: 1R01AG15962-01A1
KEYWORDS: Mental health, caregivers, African American, rural, urban
TYPE STUDY: Clinical
AMOUNT: $150,000
This study will assess the mental health and social functioning of rural and urban African-American women who provide unpaid care to an elder (65 years and older) by using a cross-sectional research design and random sample of elders. This study will identify the type and quality of caregivers' formal and informal service use. Data will be obtained through personal interviews.
TITLE: Developing Identity: An Eating Disorders Nursing Therapy NINR
P.I.: Karen F. Stein, Ph.D.
INSTITUTION: The University of Michigan at Ann Arbor, Ann Arbor, MI
GRANT NO.: 1R55NR05277-01
KEYWORDS: mental health disorders, eating disorders, behavior, self-cognition
TYPE STUDY: Clinical
AMOUNT: $100,000
The eating disorders of anorexia nervosa (AN) and bulimia nervosa (BN) are life-threatening health problems that affect as many as 5 million American females each year. Although a number of psychotherapeutic approaches to treatment have been developed, their effectiveness in producing recovery is low. One limitation of existing treatment approaches is that they tend to focus on altering symptoms of the eating disorders but do not systematically address underlying cause. The intervention program tested in this study is founded on the cognitive approach to the study of the self-concept and an empirically-supported model that suggests that the eating disorders of AN and BN stem from deficits in overall identity development. More specifically, the model suggests that the availability in memory of few positive self-cognitions and high interrelatedness among the self-cognitions contributes to the disordered attitudes and behavioral identity intervention program in fostering development of new and separate positive self-cognitions and promoting recovery from AN and BN. It will further examine the effects of these self-cognition changes on nutritional, psychological and functional health. An experimental pretest-posttest design will be used with supportive psychotherapy as the control intervention. Based on American Psychiatric Association Guidelines, nutritional counseling and medical care components of treatment will be held constant across both experimental and control intervention conditions. The effects of the intervention on self-cognitions, eating disordered attitudes and behaviors, nutritional, psychological and functional health will be monitored pre and post-intervention (immediate, 6 and 12 months post-intervention) in 150 women with threshold and subthreshold levels of AN and BN. The Structured Clinical Interview will be used to establish the eating disorder diagnosis and Ecological Momentary Assessment methodology will be used to prospectively measure eating disorder behaviors. This project extends an established program of research on the role of self-cognitions in emotional and behavioral self-regulation and holds the potential of contributing to the development of an evidence-based psychiatric nursing treatment to promote the recovery of health in women with an eating disorder.
TITLE: Effects on Children of Treating Maternal Depression NIMH
P.I.: Dr. Anne Riley
INSTITUTION: Johns Hopkins University, Baltimore, MD
GRANT NO.: 5R01MH58384-02
KEYWORDS: Mental health, maternal depression, depression, children, environment
TYPE STUDY: Clinical
AMOUNT: $50,000
Maternal depression has devastating effects on the mental and physical health of children. This project will study the influence of treating maternal depression on children ages 5-11. This project will study 150 elementary-school aged children whose mothers are depressed (50 Hispanic, 50 African American and 50 Caucasian) and 50 comparable children whose mothers are not depressed. Their mental health and functioning will be assessed by natural raters in their environments over a two-year time period that will link child functioning, symptomatology, and psychiatric disorders to mothers' symptomatology, parenting behavior, and family environment.
TITLE: Sex Differences in Self-Evaluation: Social Factors NIMH
P.I.: Eva Pomerantz, PhD
INSTITUTION: University of Illinois, Champaign, IL
GRANT NO.: R29MH57505-01A2
KEYWORDS: Gender socialization, self-evaluation, depression
TYPE STUDY: Clinical
AMOUNT: $41,049
Girls are more likely than boys to possess self-evaluative mechanisms that may heighten vulnerability to depressive and anxiety symptoms. It is hypothesized that culturally held gender stereotypes may cause parents to be more controlling in certain behavioral domains with girls than with boys. This pattern of gender socialization is expected to lead girls to be more likely than boys to possess self-evaluative mechanisms that heighten vulnerability to depressive and anxiety symptoms.
TITLE: Gender-Specific Risks for Depression in Adolescent Girls NIMH
P.I.: Sarah Bearman, B.A.
INSTITUTION: University of Texas at Austin, Austin, TX
GRANT NO.: 1F31MH12834-01
KEYWORDS: behavior, depression, adolescents, risk factors, bulimia
TYPE STUDY: Clinical
AMOUNT: $23,636
The proposed project is designed to examine a gender-specific model to explain the increased prevalence of depressive symptoms in adolescent girls compared to adolescent boys. Combining a longitudinal study which compares risk factors for depression in adolescent girls versus adolescent boys with a randomized prevention study of adolescent girls, this project has the potential to contribute significantly to the base of knowledge concerning both gender differences in rates of depression and prevention programs for depression in adolescent girls. Aim 1 is to test whether body image and eating disturbances, hypothesized to be gender-specific risk factors, emerge as prospective predictors of depressive symptoms in females, and whether this partially accounts for the relation between gender and depression. Aim 2 is to test whether a randomized experiment that reduces body dissatisfaction will lead to a subsequent decline of depressive symptoms in adolescent females, and whether manipulating body dissatisfaction will impact dieting and bulimic pathology. The aims for these two studies will be addressed through examination of prospective data from a community sample of adolescents (N=400) and a randomized experiment of a high-risk sample of adolescent females (N=60), respectively.
TITLE: Training Program in Gender and Mental Health NIMH
P.I.: Susan K. Nolan-Hoeksema, Ph.D.
INSTITUTION: University of Michigan, Ann Arbor, MI
GRANT NO.: 5T32MH19996-04
KEYWORDS: training program, mental health
TYPE STUDY: Basic
AMOUNT: $88,512
Gender differences abound in most mental health problems. A lack of interdisciplinary research and training has slowed growth and understanding of this field. This program is designed to train scholars who will conduct interdisciplinary research on gender and mental health. It will bring predoctoral and postdoctoral trainees together for work with faculty from the Departments of Psychology, Sociology, and Anthropology and from within the Schools of Medicine, Nursing, Social Work and Public Health to develop original programs to accomplish its goals: to produce new scholars to conduct basic research on gender and mental health; to encourage an interdisciplinary approach to this research; and to train excellent teachers in this field.
MUSCULOSKELETAL SYSTEMS
TITLE: Doxycycline Effect on Osteoarthritis Progression NIAMS
P.I.: Kenneth Brandt, MD
INSTITUTION: Indiana University School of Medicine, Indianapolis, IN
GRANT NO.: 5R01AR43348-03
KEYWORDS: Osteoarthritis, doxycycline
TYPE STUDY: Clinical
AMOUNT: $200,000
Osteoarthritis (OA) of the knee is the most common cause of chronic disability in this country. This group has shown that prophylactic oral administration of doxycycline (doxy) markedly reduces the severity of cartilage damage in a canine model of OA; even when therapy was initiated after cartilage lesions were established, a protective effect was apparent. Similar results have been noted in guinea pig and rabbit models of OA. The effect is associated with reduction in the levels of collagenase and gelatinase in the OA cartilage. Based on the encouraging data in animal models of OA, a randomized-placebo-controlled 30-month clinical trial will examine the effect of this drug and its ability to prevent the progression of early knee osteoarthritis in women.
TITLE: Glucocorticoids Alter the Birth and Death of Osteoblasts NIAMS
P.I.: Robert Weinstein, Ph.D.
INSTITUTION: University of Arkansas for Medical Sciences, Little Rock, AR
GRANT NO.: RO1AR 46191-01
KEYWORDS: Glucocorticoids, osteoblasts, alendronate, parathyroid hormone
TYPE STUDY: Clinical and basic
AMOUNT: $100,000
This study will characterize the effects of chronic glucocorticoid excess on several aspects of bone physiology. Patients with glucocorticoid-induced bone loss will be included. The effect of alendronate (Fosamax) and parathyroid hormone will be tested in mice for efficacy in ameliorating the effect of glucocorticoids.
NEUROLOGY
TITLE: Estrogen Induced Hippocampal Seizure Susceptibility NINDS
P.I.: Catherine Woolley, Ph.D.
INSTITUTION: Northwestern University, Evanston, IL
GRANT NO.: 5R29MS37324-02
KEYWORDS: Epilepsy, hippocampus, estradiol
TYPE STUDY: Basic
AMOUNT: $70,000
A significant proportion of women with epilepsy experience increased seizure frequency during phases of the menstrual cycle in which estradiol levels are elevated. This is termed catemenial epilepsy. Animal models of epilepsy a
