2.  Gender Differences in Drug Metabolism

As more women are included in clinical drug studies, pharmacokinetic investigations uncover significant gender-based differences in drug metabolism.  For example, in an ongoing study designed to examine the pharmacokinetics of alosetron, an investigational drug being developed by Glaxo Wellcome for irritable bowel syndrome (IBS), UNC investigators found the clearance of the drug to be 28% lower in females.  At the same dose, this difference in clearance produces a two-fold increase in alosetron levels in women as compared to men.  The use of biomarkers in such studies is likely to provide a better understanding of the basis for these differences between men and women.

Paul B. Watkins, MD (Director, General Clinical Research Center)
Kim R. Brouwer, Pharm D (School of Pharmacy)

The research interests of Drs. Watkins and Brower lie in the area of pharmacogenetics, with an emphasis the biomarker CYP3A4, a cytochrome P450 enzyme.  This enzyme represents a major pathway of drug metabolism in the liver and intestine.  There are significant individual differences in the activity of this enzyme.  A major portion of this research seeks to define the genetic and environmental factors that underly this heterogeneity.  This research is relevant to the current proposal in that many medications important to women, including most estrogens and anti-estrogens, are metabolized in the body by CYP3A4.  In addition, the available data suggest that women have higher CYP3A4 enzymatic activity than do men, which may account for differences between men and women in the response to many medications.

David A. Brenner, MD (Chief, Division of Digestive Diseases and Nutrition, Department of Medicine)

Epidemiological studies have shown that chronic alcohol-induced cirrhosis is more prevalent in women than in men.  Dr. Brenner's laboratory focuses on the complex relationship between gender and alcohol-induced liver injury.  Portal endotoxin is a biomarker strongly associated with alcohol-induced liver damage.  It may be involved in the increased susceptibility of women to liver injury.  When the female hormone estradiol is given to rats, intestinal permeability, endotoxin levels, and the sensitivity of liver macrophages (Kuppfer cells) to this biomarker all increase.  Estradiol also increases the expression of CD14, the receptor for endotoxin on Kuppfer cells.  This animal model may help to explain the gender-based differences in alcohol-related liver disease.

3.  Integrins, Extracellular Matrix and Signal Transduction

The discovery of integrins and their ligands in the extracellular matrix (ECM) has led to many key advances in our understanding of cell adhesion.  Such research is relevant to a number of women's health issues.  Examples include the molecular mechanism of embryo implantation, the gender-differences in vascular disease, and the factors involved in the spread of cancer.  The use of biomarkers is fundamental to the research in each of these areas.

Bruce A. Lessey, PhD, MD (Department of Obstetrics and Gynecology)

There exists at UNC an outstanding core of clinical and basic scientists who are interested in implantation research and uterine biology.  Dr. Lessey's laboratory studies the role of integrins in endometrial growth and development and the changes that increase the receptivity of the uterus to embryo implantation.  Dr. Lessey has found that certain integrins are present in the endometrium at the time that embryos attach.  He is investigating the use of these biomarkers in identifying women at risk for infertility or recurrent pregnancy loss.  Applications of these studies include the general improvement in reproductive potential, a better understanding of "unexplained" infertility, and the development of model systems to study implantation biology.  Understanding uterine receptivity could also lead to novel methods of contraception that target the endometrium.  Finally, this work could provide new insights into the changes that occur in endometrial cancer.

David G. Kaufman, MD (Department of Pathology and Lab Medicine)

Dr. Kaufman's research employs cultured human endometrial cells to study cell-cell interaction in normal and malignant cells.  He has developed in vitro cell models to investigate the role of integrins, ECM and growth factors in endometrial growth and differentiation.  Using these models, Dr. Kaufman studies the mechanisms of cell-cell communication.  Finally, in an attempt to better understand the development of diseases like cancer, Dr. Kaufman's laboratory investigates the signal transduction pathways that regulate the flow of information from outside to inside the cell.

Leslie V. Parise, PhD (Department of Pharmacology)

Dr. Parise is well recognized for her research in the area of cell surface adhesion receptors and cell signaling.  Her work has provided fundamental information on the nature of integrin-related signal transduction pathways in platelets.  For example, she has mapped collagen-mediated signaling pathways that lead to integrin a IIb 3 activation.  Dr. Parise's laboratory has been a leader in the identification of novel intracellular integrin binding proteins, such as CIB, that appear to modulate integrin function.  Another focus of her work relates to integrin-mediated motility and invasion of breast cancer cells.  Dr. Parise has also collaborated with Dr. Lessey on projects involving the expression of integrins in human endometrial stromal cells during the process of decidualization, and with Dr. Orringer on several adhesion-related sickle cell projects.

Gilbert C. White II, MD (Director, Center for Thrombosis and Hemostasis; Department of Medicine)

The focus of Dr. White's research is on the role of blood platelets in hemostasis and atherothrombosis.  Because platelets play such an important role in the thrombosis that occurs during pregnancy, in postmenopausal atherosclerosis, in preeclampsia syndromes, and in von Willebrand's disease (a common cause of abnormal menstrual bleeding in women), he is ideally suited to be a BIRCWH mentor.  Certain integrins, including a IIb 3, mediate platelet adhesion and aggregation, and Dr. White's lab seeks to elucidate the sequences in the extracellular domains of a IIb 3 that mediate its interaction with fibrinogen.  Other projects study integrin and cAMP/G protein-mediated signaling.  An understanding of the mechanisms involved in these various pathways may provide new ways to regulate platelet function for the treatment of atherothrombotic disorders in women.

4.  Nutrition and Diseases in Women

Steven H. Zeisel, MD, PhD (Chairman, Department of Nutrition, School of Public Health)

Dr. Zeisel's research focuses on nutrients and their influence on brain development and carcinogenesis.  Current lines of investigation include:  1) examination of critical periods in brain development associated with choline availability; 2) the role of nutrition in the migration and death of cells in the memory centers of the brain; 3) the effect of choline and antioxidants on carcinogenesis; and 4) human clinical trials on the safety and efficacy of genistein and diadzein for the treatment of prostate and breast cancer.  This latter line of investigation, which is particularly relevant to multiple themes in this proposal, makes Dr. Zeisel an excellent example of the multidisciplinary nature of the mentors in our pool.

Barry M. Popkin, PhD (Department of Nutrition, School of Public Health)

Dr. Popkin has a special interest in women's health.  His research focuses on trends in long-term dietary and nutritional status.  He specializes in the integration of biomedical and social science in studying these trends, their determinants, and their consequences.  He has an active research program that focuses on large, population-based studies including one on gender differences in body fat as a function of nutrition.  He also collaborates with nutrition researchers around the world.

5.  Recurrent Pregnancy Loss

Recurrent pregnancy loss (RPL) is a major health problem affecting women of reproductive age.  While chromosomal and uterine abnormalities and endocrinologic alterations can cause RPL, most cases go unexplained.  However, recent studies have found acquired or inherited thrombophilia to be present in up to 50% of women with RPL.  Thrombophilia also occurs in women with other vascular placental abnormalities such as preeclampsia, placental abruption, and intrauterine fetal growth restriction.

Robert A. Roubey, MD (Department of Medicine)

Dr. Roubey investigates antiphospholipid syndrome (APS), an autoimmune disorder characterized by arterial and venous thrombosis and recurrent fetal loss.  It is estimated that primary APS accounts for up to 20% of all episodes of venous thrombosis, a third of strokes in patients under the age of 50, and 15% of recurrent fetal losses.  Dr. Roubey hypothesizes that autoantibodies are not only a biomarker of this syndrome, but contribute directly to thrombophilia and the resulting fetal loss.  Further research in Dr. Roubey's laboratory is aimed at defining the mechanisms by which these antibodies participate in thrombotic events.

6.  Sexually Transmitted Diseases

Sexually transmitted diseases (STDs) represent complex infectious processes with broad implications for the health of women, and there is increasing interest in the use of biomarkers in this field.  Since STDs have been associated with increased risk of both HIV infection and certain cancers, early detection and treatment is essential.  UNC, which is an international leader in the study of STDs, has been designated a STD Clinical Trials site by the NIH.  The study of STDs is yet another example of exceptional interdisciplinary research at UNC that employs the use of biomarkers for both diagnosis and assessment of therapeutic response.

William K. Kaufmann, PhD (Department of Pathology and Lab Medicine)

Dr. Kaufmann's laboratory studies pathways of DNA metabolism that ensure complete and accurate replication of the genome.  Using primary and secondary cultures of human cells, he studies the role of selected genes in preservation of genomic integrity.  His work on cervical cancer and human papilloma virus (HPV) has demonstrated that destabilization of the DNA structures by viral proteins may contribute to the development of cervical neoplasia.  These studies have led to the hypothesis that chromosomal instability in cervical cancer is a function of the number of cell division cycles that HPV-infected keratinocytes undergo before immortalization.  Dr. Kaufmann is testing this model by studying cervical scrapings and biopsies for expression of telomerase and chromosomal instability in HPV-infected cells.  Studies will determine whether telomerase expression and/or chromosomal instability can be used as biomarkers to predict progression from dysplasia to cervical intraepithelial neoplasia.

Charles M. Vanderhorst, MD (Department of Medicine)

Dr. Vanderhorst, a leading investigator in the area of AIDS research, directs the UNC AIDS Clinical Research Unit.  This group studies HIV in women from many different perspectives.  For example, in collaboration with the Carolina Pediatric AIDS Unit and the North Carolina Children's AIDS Network, Dr. Vanderhorst is involved in studies of maternal-child HIV transmission.  Other women's health-related efforts include prevention of cervical carcinoma in HIV-positive patients, development of new assays for early diagnosis, the prevalence of HIV resistance in women, and collaborations with School of Nursing on strategies to cope with symptoms of HIV and to educate African American women about HIV.  New biomarkers to diagnose trichomonas, Neisseria gonorrhoeae, ureaplasma and chlamydia in HIV-positive women are also under development.

Ronald Swanstrom, PhD (Director, UNC Center for AIDS Research [CFAR])

Dr. Swanstrom's laboratory is involved in the study of HIV and related viruses in primate models with particular focus on development of vaccines and mechanisms of therapeutic resistance in HIV infections.  He is a noted expert on the synthesis, processing, and assembly of viral proteins.  In addition, as director of the Center for Aids Research (CFAR), Dr. Swanstrom is involved in many clinical trials including the prevention of AIDS in neonates and the association between accelerated cervical dysplasia and HIV infection.

Myron S. Cohen, MD (Director, UNC Center for Infectious Disease; Chief Division of Infectious Diseases, Department of Medicine)

Myron Cohen's research is focused on the pathobiology of Neisseria gonorrhoeae, with emphasis on its interaction with host defenses.  Since gonococci are strictly limited to a human host cell, animal models have not proven to be satisfactory.  For this reason, Dr. Cohen's laboratory has established a human challenge model for gonorrhea.  Using this model, Dr. Cohen and his colleagues have conducted GCRC-based studies of the phenotypic variation of gonococci in vivo.  He has also employed isogenic mutant organisms to define the factors that determine gonococcal virulence.  Trainees in Dr. Cohen's laboratory are broadly exposed to many research skills, including humoral and cellular immunology, molecular biology, and the methods and ethics of human research.

Frederick P. Sparling, MD (Director, North Carolina Sexually Transmitted Infections Research Center; Department of Medicine)

Neisseria gonorrhea is a serious threat to the reproductive health of women.  Dr. Sparling studies the structure, function, regulation and vaccine potential of outer membrane proteins of the gonococcus.  His research involves the cloning of genes involved in transferring binding proteins, lactoferrin binding proteins, hemoglobin receptors, and the major iron-repressed outer membrane protein FrpB.  He is also interested in the pathogenesis of proteins that are only expressed in the presence of iron, as evidence now suggests that these proteins may be critical for attachment of and invasion by this microorganism.  Vaccine development is a major focus of the research being conducted jointly by Drs. Sparling and Cohen.  This work is being conducted on the UNC General Clinical Research Center.  Scholars under Dr. Sparling's mentorship will be exposed to techniques of molecular biology, cell biology, and immunology, including vaccine development.