BIRCWH Mentors

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Maryland's Organized Research Effort in Women's Health (MORE-WH)

Lead Mentors

Life Changes in Women's Health

Eugene D. Albrecht, Ph.D., Professor, Department of Obstetrics, Gynecology & Reproductive Sciences, School of Medicine. A major area of interest in Dr. Albrecht's research laboratory is the steroid hormone regulation of angiogenesis in the human and nonhuman primate endometrium. Angiogenesis is essential to the development and cellular differentiation of the endometrium for potential implantation. He has recently shown that expression of the angiogenic factor, vascular endothelial growth/permeability factor (VEG/PF), was markedly decreased in glandular epithelial and stromal cells isolated by laser capture microdissection from the endometrium of ovariectomized baboons. Estradiol administration to ovariectomized baboons, in levels which replicated the normal proliferative phase of the menstrual cycle, restored endometrial VEG/PF mRNA and protein expression and vascularization to normal while progesterone had limited effect. Thus, estrogen is the principal ovarian steroid hormone that regulates and sustains endometrial VEG/PF formation to promote neovascularization and development of the endometrium during each menstrual cycle. Because angiopoietin-1 and -2 have essential roles in working with VEG/PF for the development and maturation of a new vascular bed, ongoing studies in his laboratory are determining the action of estrogen and progesterone on endometrial angiopoietin-1 and -2 expression. A soluble truncated receptor for VEG/PF flt-1 is also being delivered to baboons to test the hypothesis that the regulatory effect of estrogen on endometrial angiogenesis/microvessel permeability is mediated by VEG/PF. These studies are expected to show that estrogen and progesterone regulate angiogenesis in a cell- and menstrual cycle stage-specific manner for the development, maturation, and remodeling of the endometrial vascular system. Because improper VEG/PF expression and vascularization of the endometrium are associated with endometriosis, dysfunctional bleeding and menorrhagia, the present study is expected to lead to a critical understanding of the events leading to infertility.

Larry D. Anderson, Ph.D., Professor, Department of Anatomy & Neurobiology, School of Medicine. Currently, four areas of reproductive research are actively pursued in the laboratory of Dr. Anderson: 1) in conjunction with the Depleted Uranium (DU) Program at the Baltimore Veterans Administration Medical Center, the lab is assessing the reproductive health status of Gulf War and Operation Iraqi Freedom veterans exposed to depleted uranium munitions; 2) examination of the interaction of estrogen and various angiogenic factors to promote/inhibit blood vessel formation in the uterus and placenta of the babbon in vivo and human, uterine, endometrial cells in vitro; 3) examination of the importance of optimal fetus exposure to maternal estrogen during various stages of pregnancy to oechestrate the organization and full complement of fetal germ cells in the gonads of male and female baboons; and 4) assessing spermatozoa with semen analysis in a number of non-human captive species, particularly endangered species and species for human consumption.

Gloria E. Hoffman, Ph.D., Professor, Department of Anatomy & Neurobiology, School of Medicine. The research in Dr. Hoffman's laboratory has for many years focused on issues of the CNS control of reproductive function. Currently, this research has evolved to a study of the processing of excitatory stimuli to the neurons that contain luteinizing hormone releasing hormone (LHRH or gonadotropin releasing hormone, GnRH) and trigger ovulation. At the system’s levels, studies are examining the neural circuits that transduce steroid signals to the LHRH neurons. The LHRH neurons are an essential component of reproductive function and marked increases in their activity accompany the preovulatory LH surge. The study of LHRH neurons has been particularly challenging since they are diffusely organized within the forebrain, small in size, and few in number, making conventional approaches for studying their activity impractical. Dr. Hoffman's laboratory has determined that the immediate early genes, c-fos, and c-jun are expressed in LHRH neurons during an LH surge. The appearance of immediate early gene proteins accurately reflects LHRH stimulated activity. Using this approach, this laboratory has examined the dynamics of LHRH activation, participation of steroid hormones in this process, and the role of selected afferents containing catecholamines, neuropeptides and excitatory amino acids in regulating LHRH activity. Recently, attention has shifted from where immediate early gene proteins are expressed to what changes in gene expression within neuroendocrine neurons are triggered by immediate early gene expression. In those studies, the expression of a second transmitter in the LHRH neurons, galanin, is the target of investigation. In addition, the laboratory has addressed the neuronal changes in the prolactin regulatory neurons during lactation. New quantitative non-radioactive in situ hybridization methods have been devised and studies are now underway to examine the neural mechanisms underlying suckling-induced synthesis suppression of the tyrosine hydroxylase, the rate-limiting enzyme for production of the prolactin inhibiting factor, dopamine. A separate, although related direction in Dr. Hoffman’s laboratory focuses on the consequences of ovarian function on the injured brain. These studies examine the role that ovarian hormones play in seizure-induced brain damage, and neuronal damage induced by CNS inflammatory disease experimental allergic encephalitis.

Robert Koos, Ph.D., Professor, Department of Physiology, School of Medicine. Dr. Koos' research is focused in three areas: angiogenesis in the ovary and uterus; roles of growth factors VEGF and FGF-10; estrogen, estrogen receptors and the peptide hormone relaxin. The goal of Dr. Koos' research in angiogenesis is to understand the mechanisms that control developmental events, particularly angiogenesis (the growth of new blood vessels) in the ovary and uterus. Blood vessels repeatedly grow and regress during the rapid, hormonally regulated development of these tissues during the reproductive cycle and pregnancy, making them excellent systems for the study of this fundamental developmental process. He has concentrated his efforts on examining the roles of fibroblast growth factors (FGFs) and vascular endothelial growth factor/vascular permeability factor (VEGF) in this process. Using quantitative reverse transcription-polymerase chain reaction (RT-PCR), he has shown that VEGF expression increases markedly following the ovulatory signal, and immediately before the onset of follicular edema, suggesting that VEGF plays a role in follicle rupture as well as vascularization of the CL. Dr. Koos has also shown that VEGF expression is rapidly stimulated by estrogen in the uterus, and that the increase immediately precedes uterine edema, suggesting that VEGF induces this response. He is now exploring the molecular mechanisms involved in the regulation of VEGF expression by estrogen using formaldehyde cross-linking/chromatin immunoprecipitation (X-ChIP) to map the sites in the promoter region of the VEGF gene through which estrogen acts.

FGF-10 is a growth factor that is expressed in the ovary, and expression correlates with the formation of mature follicles. To understand the role that FGF-10 plays in this process Dr. Koos is transplanting the ovaries from newborn FGF-10 knockout mice to host animals, in which the ovary can mature. The preliminary results of these studies indicate that the absence of FGF-10 completely disrupts normal follicle growth.

Estrogen regulates the growth and differentiation of the uterus and other target tissues via binding to estrogen receptors (ERs), which are members of the nuclear receptor family of transcription factors. Two forms of ER are now known to exist: ERalpha and ERbeta. To gain further insight into the actions of estrogen in target tissues and into the role of ERbeta in those actions, Dr. Koos recently examined its effects and those of relaxin, a ligand-independent activator of ERs, on the expression of ERbeta1 and ERbeta2 mRNA in the uterus in vivo. Estrogen markedly decreased the steady-state levels of the mRNAs for both and relaxin induced a similar rapid down-regulation. In marked contrast to the effects on ERbeta, estrogen rapidly increased VEGF mRNA levels. His studies are relevant to the mounting evidence that decreased ERbeta may contribute to the development of cancer, in that they demonstrate that estrogen itself induces such a decline.

Relaxin is a peptide hormone produced by the ovary that belongs to the same family as insulin and insulin-like growth factors. It plays important roles in the growth and remodeling of the reproductive tract during pregnancy and in preparation for birth. Interestingly, many of relaxin’s effects closely resemble those of estrogen. Dr. Koos has demonstrated that relaxin activates ERs by blocking relaxin’s ability to stimulate uterine edema with a drug that blocks ER action. These novel studies suggest that relaxin may play a role in the growth of so-called “estrogen-dependent” cancers, such as breast cancer.

Margaret M. McCarthy, Ph.D., Professor, Department of Physiology, School of Medicine. The developing brain remains a source of fascination and awe to neuroscientists and lay men alike. Less known to many is the bipotentiality of the developing brain, capable of taking on a masculine or feminine phenotype in equal measure. Body gender is determined by genes on the Y chromosome while the gender of the brain is dictated by the hormones produced by the gonad during a perinatal sensitive period. Events occurring as part of normal brain development are profoundly and permanently altered by the neonatal hormonal milieu, making this a useful model system of brain development. In particular, hormones modulate the fundamental yet still poorly understood processes of neurite outgrowth, synaptogenesis and naturally occurring cell death or apoptosis. Elucidating the cellular and molecular mechanisms mediating steroid-induced brain differentiation is the principle goal of Dr. McCarthy's research program.

The amino acid transmitter, GABA, mediates most synaptic inhibition in the mature brain but is actually the principal source of excitation in developing neurons and activates voltage gated calcium channels, causing a precipitous rise in intracellular calcium (Ca2+). Changes in free cytosolic Ca2+ activate multiple signal transduction pathways to alter cell function. Dr. McCarthy found that the hormonal profile of neonatal males results in GABA being more depolarizing, thereby doubling the magnitude of Ca2+ influx, and also extends the developmental period during which GABA exerts an excitatory action (Perrot-Sinal et al., Endocrinology 2001). She further demonstrated that the transduction sequelae of GABA are opposite in developing male and female brains. The transcription factor CREB is activated (phosphorylated) by GABA in males but is inhibited (dephosphorylated) by GABA in females. The activation of kinases versus phosphatases by the same transmitter, GABA, represents a major divergence point in the pathway to a male versus female brain. Dr. McCarthy's current research investigates the consequences of this gender-specific difference for cellular differentiation and adult brain function.

Istvan Merchenthaler, M.D., Ph.D., Sc.D., Professor, Departments of Epidemiology & Preventive Medicine and Anatomy and Neurobiology, School of Medicine. Dr. Merchenthaler's research focuses on the following: 1) the pathomechanism of hot flashes including the role of ovarian steroids, neurotransmitters and neuropeptides; 2) neuroprotection with estrogen including the role of estrogen receptor-a (ER-a and (ER-; 3) the development of CNS-selective estrogens for hormone replacement therapy; and 4) central regulation of reproduction including the role of stress, ER-a, enkephalin and galanin in pulsatile luteinizing hormone-relseasing hormone (LHRH) secretion and ovulation.

Adverse Conditions and Diseases in Women

Claudia R. Baquet, M.D., Associate Professor, Department of Epidemiology & Preventive Medicine and Associate Dean for Policy and Planning, School of Medicine. The Cancer Disparities and Intervention Research Program is directed by Claudia R. Baquet, MD, MPH, and co-directed by Sandra E. Brooks, MD. Dr. Baquet’s program of research includes The Maryland Special Populations Cancer Research Network (MSPN), funded by the National Cancer Institute (NCI-1UO1-CA86249). This initiative supports the development, implementation and evaluation of a sustainable and robust infrastructure (the “Network”) to promote cancer awareness and support cancer control activities in minority and medically underserved communities in Maryland. The focus includes community-based participatory research in cancer disparities, the training of minority investigators through grant writing workshops, the mentoring of junior investigators, and the funding of pilot studies. Additional objectives include establishing research priorities and planning collaborative developmental projects with relevant NCI divisions and research partners, and developing competitive grant applications stemming from the pilot projects. The MSPN will give scholars in the MORE-WH Program opportunities to become involved in cancer disparities research and outreach activities with minority and medically underserved communities in Maryland. Involvement in cancer control research will also be available through the Maryland Statewide Health Network (MSHN) of the University of Maryland Medical System, also directed by Dr. Baquet. The MSHN is a community-based, statewide and regional infrastructure, which supports cancer and tobacco-related disease prevention and control activities. Some of the ongoing activities include a telemedicine program, increasing access and participation in clinical trials, and developing Best Practices Models.

Angela M.H. Brodie, Ph.D., Professor, Department of Pharmacology & Experimental Therapeutics, School of Medicine. Dr. Brodie’s research interests focus on steroid biochemistry, reproductive endocrinology, and the endocrinology of prostate cancer as well as breast cancer and other estrogen-mediated diseases. Dr. Brodie developed the first selective aromatase inhibitors for the treatment of breast cancer. In particular, formestane (4-hydroxyandrostenedione) was the first selective aromatase inhibitor to be used clinically and at that time was the only new drug specifically designed for the treatment of breast cancer in 10 years. Formestane was released for worldwide use in 1994. Dr. Brodie’s current research interests include the development of a novel pre-clinical model for determining effective treatment strategies to aid in the design of clinical trials. The model is also being used to investigate changes in gene expression during aromatase and antiestrogen treatment. These studies could help understand the mechanisms involved in drug resistance and lead to new ways to improve treatment and prevention.

Amy F. Fulton, Ph.D., Professor, Department of Pathology and Program in Oncology, School of Medicine. The Cyclooxygenase (COX) enzyme is commonly overexpressed in many solid tumors, including breast cancers. COX expression is emerging as a risk factor for more aggressive disease. Dr. Fulton has several projects that would be appropriate for an interdisciplinary research project. (1) How is high level expression of COX induced in tumors. Dr. Fulton has preliminary evidence that the expression of the COX gene is regulated by hypermethylation of the COX promoter. This project will extend these studies to establish a definitive mechanism of promoter regulation. (2) Dr. Fulton also has data indicating that selective pharmcologic inhibitors of COX inhibit growth and metastasis of malignant breast tumors. Using gene expression studies and examination of cell response pathways, she will determine the mechanism(s) by which these drugs exert therapeutic activity. (3) Cyclooxygenase metabolites have profound effects on immune function. She is studying how COX inhibitors modulate antitumor immune effector function.

Susan K. Keay, M.D., Ph.D., Associate Professor, Department of Medicine, School of Medicine. Interstitial cystitis (IC) is a chronic bladder disorder for which the etiology is unknown. The most consistent histologic abnormalities in IC are ulcerations or multiple tears in the bladder epithelium. Dr. Keay has discovered an antiproliferative factor (APF) in the urine of IC patients that inhibits the proliferation of bladder epithelial cells in vitro. This factor regulates the production of specific epithelial cell growth factor levels, resulting in significantly decreased urine levels of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and increased levels of epidermal growth factor (EGF), insulin-like growth factor 1 (IGF1), and insulin-like growth factor binding protein 3 (IGFBP3). Current research projects include determining the structure of the APF, determining the mechanism by which APF regulates the production of epithelial cell growth factors, and developing a mouse model of IC based on the APF.

James I. Koenig, Ph.D., Professor, Department of Psychiatry, School of Medicine. The brain is a plastic structure that changes as our environmental situations change. Research in Dr. Koening's laboratory is directed at understanding the neurochemical mechanisms in the brain that facilitate adaptation to a new environment and the maladaptive changes that may occur in the brain during prolonged periods of stress. Chronic stress appears to trigger a cascade of events by way of alterations in hypothalamic-pituitary-adrenal axis activity that may be the harbinger of future psychopathological conditions, such as depression or anxiety. Understanding how stress and hormones related to stress influence the brain may be of great importance in creating new treatment strategies for depression and anxiety that are known to exhibit a sexually dimorphic pattern of incidence.

Denise M. Korniewicz, Ph.D., Professor, School of Nursing. Dr. Korniewicz's expertise is infectious disease and infection control. She has had several grants funded related to health care worker safety and patient safety. Students who work with Dr. Korniewicz have developed an interest in the risk factors associated with nosocomial infection rates, health care worker safety issues and patient safety concerns. Specifically, in her area of expertise, further investigation into the risk factors associated with emerging and re-emerging infections among women would be an ideal expansion of her research. Therefore, mentoring young faculty in the area of women’s health and infectious disease risk factors is not only timely but also much needed.

Jay S. Magaziner, Ph.D., M.S.Hyg., Professor, Department of Epidemiology & Preventive Medicine, School of Medicine. Dr. Magaziner’s interdisciplinary training in gerontology, enhanced by his training in epidemiology, provides a unique perspective and special skills which he brings to his teaching and research. His research is focused on the consequences of hip fracture, health and long-term care, and methods for studying older populations to identify ways of enhancing functioning and improving the quality of life of older persons. His work on hip fracture has earned Dr. Magaziner a MERIT award from the NIA to evaluate a wide range of medical and psychosocial consequences of hip fracture. Recently this work has expanded to examine interventions for improving post-fracture bone, muscle and functional status and to chart the sequelae of hip fracture. Dr. Magaziner teaches a graduate course in epidemiology of aging, and is PI/director of a T32 pre- and post-doctoral training program in the Epidemiology of Aging supported by the NIA and of a T32 post-doctoral training program in primary care research from HRSA. He co-directs the newly established doctoral program in gerontology, which draws on faculty and resources from two UM campuses.

Antonino Passaniti, Ph.D., Assistant Professor, Departments of Pathology and Biochemistry & Molecular Biology, School of Medicine. Research efforts in Dr. Passaniti's laboratory have targeted endothelial cells (EC) and tumor vasculature for therapeutic application. Since angiogenesis is an important component of tumor growth, progression, and metastasis, his laboratory has investigated the mechanisms of endothelial cell survival and differentiation. While at the NIH, he developed a quantitative assay to measure angiogenesis in vivo and to test inhibitors of angiogenesis. In particular, he has been interested in transcription factor regulation of angiogenesis. He is currently studying the role of the transcription factor Runx2 (core binding factor alpha) in EC interactions with the extracellular matrix, with other EC, and in angiogenesis. Dr. Passaniti's current hypothesis is that this transcription factor is expressed in neovasculature and may regulate the expresssion of downstream genes involved in EC migration and angiogenesis. He is testing this hypothesis by using Runx2 dominant negative and overexpression vectors to generate stable EC transfectants. Since this factor has been shown to regulate protease expression in breast cancer cells, he is also examining the effect of dominant negative Runx2 vectors on breast tumor cell invasion, a process essential to cancer metastasis.

Dr. Passaniti has established collaborations with several investigators at the University of Maryland, Greenebaum Cancer Center, especially Dr. Judith Karp who is co-ordinating anti-angiogenesis clinical trials and correlative studies, and research faculty in the Programs in Oncology, Experimental Therapeutics (Dr. Douglas Ross) and the Program in Cell & Molecular Biology (Dr. Peter Melera). In addition, Dr. Niharika Khanna (Department of Family Medicine) and Dr. Passaniti are collaborating on a project to determine whether the expression of the angiogenic factor VEGF can be used as a correlative marker of cervical dysplasia which is prognostic for cervical cancer. Dr. Passiniti is a member of the Breast Cancer Group (Dr. Kate Tkachuk; Dr. Brad Carter) and interacts with Drs. Amy Fulton (Pathology) and Angela Brodie (Pharmacology).

Renee Royak-Schaler, Ph.D., M.Ed., Associate Professor, Department of Epidemiology & Preventive Medicine, School of Medicine. Dr. Royak-Schaler is a health psychologist whose research focuses on disparities in cancer screening and early detection. Before coming to the University of Maryland, she was the Director of the Division of Behavioral Sciences and Leader of the Population Based Cancer Control Program at the American Health Foundation Cancer Center (AHFCC) in New York. Under her direction, the AHFCC developed interdisciplinary studies designed to investigate the behaviors and biological markers associated with breast cancer outcomes in minority populations. Her ongoing studies investigate the psychosocial and behavioral factors that influence the risk perceptions, screening practices, and cancer outcomes of minority women. She was Principal Investigator of the PARTNERS in Breast Cancer Education Program (NCI-RO1-CA-68336, 1996-2000), a church-based initiative for African American women designed to promote accurate risk perceptions, prompt symptom care, and effective communication about breast cancer with primary care providers. Prior to leaving the AHFCC, she was Principal Investigator of the CUNY-AHFCC Partnership, Training Minorities in Bio-behavioral Cancer Research (NCI-P20-CA91401, 4/01/01- 3/31/04). This project was funded by the NCI to train minority faculty and graduate students at the City University of New York in cancer prevention and control research. She continues on this training partnership as Co-Principal Investigator of a funded pilot study, Targeting Breast and Colorectal Cancer Risk Communication for African American and Hispanic Populations in East Harlem (NCI-P20-CA91401, 6/01/01-5/31/02). Dr. Royak-Schaler is collaborating with the Crozer-Keystone Health System in Philadelphia, PA to develop evidence-based methods for providers to assess, communicate, and reduce cancer risk factors with their minority patients in primary care practices.

Robert Schwarcz, Ph.D., Professor, Department of Psychiatry, School of Medicine. Dr. Schwarcz's laboratory is primarily concerned with the molecular and cellular mechanisms that underlie nerve cell death in the central nervous system. In particular, his work is related to the idea that "excitotoxic" processes, triggered by an overstimulation of excitatory amino acid receptors, are causally involved in the pathophysiology of several neurological and psychiatric diseases. Work in his laboratory focuses especially on the potential role of excitotoxic mechanisms in Huntington's disease, temporal lobe epilepsy and schizophrenia. Since the excitotoxic hypothesis implies that antagonists of excitatory amino acid receptors ought to prevent or arrest neurodegeneration and thus hold promise as novel therapeutic agents, work in the laboratory also involves anti-excitotoxin-based drug discovery programs. Many of these studies are concerned with the neurobiology of quinolinate (QUIN) and kynurenate (KYNA), two brain constituents with neuroexcitatory (and excitotoxic) and neuroinhibitory and (neuroprotective) properties, respectively. Both QUIN and KYNA are breakdown products of the essential amino acid tryptophan. Using a combination of biochemical, histological and electrophysiological techniques, work in his laboratory has elaborated many of the characteristics and control mechanisms that govern the function of QUIN and KYNA in the brain. Ongoing in vivo and in vitro studies are designed to 1). Identify possible abnormalities in QUIN and KYNA metabolism in excitotoxic brain diseases, 2). Further define the neurobiology of QUIN and KYNA by manipulating their metabolism with new and specific pharmacological agents and by using molecular biological techniques; these studies include assessment of gender differences and the effect of sex hormones on cerebral QUIN and KYNA metabolism, and 3). Use novel "kynrenergic" drugs in order to influence normal and dysfunctional excitatory neurotransmission in the central nervous system.

Lisa M. Shulman, M.D., Associate Professor, Department of Neurology, School of Medicine. As a member of the Parkinson’s Study Group, Dr. Lisa Shulman is Principal Investigator of a multicenter pilot clinical trial to evaluate the effects of estrogen replacement therapy in postmenopausal women with Parkinson’s disease. The study will assess safety, tolerability and efficacy of ERT including potential effects on motor function, levodopa-related complications (motor fluctuations and dyskinesia), and cognitive/ behavioral functions. Issues of recruitment of women for clinical trials in general, and menopause/estrogen replacement trials in particular, will be explored. Dr. Shulman is planning future trials to directly study estrogen’s effects on levodopa pharmacokinetics and pharmacodynamics.

Katherine H. Tkaczuk, M.D., Associate Professor, Departments of Medicine and Oncology, School of Medicine. Dr. Tkaczuk is a full-time clinical faculty member at the University of Maryland Greenebaum Cancer Center. Her research interests are clinical and focused on the development of new therapies for early and advanced stage breast cancer. She has been involved in the development and conduction of multiple Phase I, II and III clinical trials in patients with breast cancer and other solid tumor malignancies. She was principal investigator on several investigator-initiated clinical trials such as: Phase I study of Taxotere and Topotecan in solid tumor malignancies, Phase I study of Taxol, UFT and Leucovorin in solid tumor malignancies, Phase II study of Taxotere and Topotecan in patients with metastatic breast cancer, and Phase II study of Taxotere and Theratope vaccine in patients with metastatic breast cancer.

Gender Differences in Pain

Mona Baumgarten, Ph.D., Associate Professor, Department of Epidemiology & Preventive Medicine, School of Medicine. Dr. Baumgarten is currently engaged in a program of research designed to identify risk factors for pressure ulcers in frail elderly hospital patients. Pressure ulcers represent a common adverse outcome in this population (the majority of whom are women), and have a significant negative impact both in terms of patient suffering and cost of care. Dr. Baumgarten is Principal Investigator of a study (funded by the National Institute on Aging) whose aim is to examine pressure ulcer risk in relation to various factors to which elderly medical patients admitted through the Emergency Department (ED) are exposed early in their hospital stay. Dr. Baumgarten is also PI of a study (funded by the National Institute on Arthritis and Musculoskeletal and Skin Diseases), the aim of which is to examine pressure ulcer risk among hip fracture patients in the context of recent changes in the duration and location of acute and postacute care. Dr. Baumgarten’s research, by addressing a common and serious adverse outcome for frail elderly hospital patients, has the potential to improve the quality of life of elderly women.

Gary Fiskum, Ph.D., Professor and Research Director, Department of Anesthesiology, School of Medicine. Dr. Fiskum investigates molecular mechanisms of neural cell death associated with acute neurodegenerative disorders, e.g., stroke, and in chronic neurodegenerative diseases, e.g., Parkinson’s disease. He focuses on oxidative stress, mitochondrial dysfunction, and apoptotic cell death, and has developed neuroprotective interventions based on these mechanisms of injury. Currently, he is collaborating with Drs. Gloria Hoffman and Anne Murphy (Anatomy and Neurobiology), Dr. Krish Chandrasekaran (Anethesiology), and Dr. Courtney Robertson (Pediatrics) on a project supported by the Department of Defense that investigates mechanisms of neuroprotection by estrogens and progesterone. This project involves the use of animal models of status epilepticus and traumatic brain injury and cell culture models of excitotoxicity and apoptosis. They are pursuing mechanistic hypotheses related to antioxidant, anti-excitotoxic, and anti-apoptotic actions of estrogens and progesterone. In the future, they plan to also pursue the neuroprotective actions of gonadal hormones in other models of neurodegeneration, including global cerebral ischemia and environmental toxin models of Parkinson’s disease.

Michael S. Gold, Ph.D., Assistant Professor, Department of Oral & Craniofacial Biological Sciences, Dental School. One of the main focuses of Dr. Gold's lab is the identification of mechanisms underlying gender differences in nociceptive processing. Specifically, he is investigating the influence of estrogen on ionic mechanisms controlling excitability of sensory neurons as well as the impact of estrogen on inflammation-induced changes in excitability. He has focused this line of investigation on sensory neurons innervating structures for which there are pronounced gender differences in the expression of pain syndromes: the temporomandibular joint (TMJ) and the colon. Behavioral data from animals indicate that estrogen not only increases the response to noxious stimulation of these two structures, but increases the magnitude of inflammation-induced changes in nociceptive processing. Electrophysiological data suggests that these estrogen-induced effects are mediated in part through changes in sensory neurons. He is presently in the processes of characterizing the ionic mechanisms underlying the influence of estrogen on primary afferent neurons.

Joel D. Greenspan, Ph.D., Associate Professor, Department of Oral & Craniofacial Biological Sciences, Dental School. Dr. Greenspan's laboratory focuses on the neural mechanisms of somesthesis, and physiological factors that influence our perception of touch, temperature, and pain. He has several active areas of investigation, which allows him to gain different perspectives of this complex field:

I. The role of cerebral cortical processing in the various aspects of somesthesis. A. Brain activation studies (both PET and fMRI) have identified multiple regions in the parietal and insular lobes that respond to somesthetic stimulation. He combines psychophysical and fMRI brain imaging techniques to determine what functional roles these various brain regions play in different aspects of somesthetic perception. Both the initial processing regions of the cortex (S1 and S2), and the subsequent processing regions (posterior parietal, insular, and cingulate cortices) are of interest, particularly in terms of their relationship to sensory-discriminative vs. affective aspects of somesthesis. B. Dr. Greenspan has used a combination of high-resolution MRI and psychophysical evaluations to associate specific sensory abnormalities with sites of cerebral pathology in individuals with localized cerebral lesions. He is now combining such "lesion analysis" with functional brain imaging, in order to better understand the functional changes that occur within the somatosensory system. Of particular interest is the phenomenon of "central pain"--a debilitating and poorly treated pain condition that results from certain brain lesions, principally strokes involving the somatosensory pathways. C. Dr. Greenspan is evaluating the neural changes that occur following acupuncture and placebo analgesia using fMRI. He seeks to identify the specific cerebral structures that are engaged as a result of using these analgesic manipulations, as well as identifying those pain-related cerebral structures that are suppressed.

II. The bases for gender differences in pain. It has become increasingly evident that there is some degree of gender difference in pain sensitivity, both in laboratory animals and in humans. Dr. Greenspan is examining this issue in human subjects by evaluating which CNS mechanisms of nociceptive processing show sex differences. He is also examining the question of whether those aspects of nociceptive processing that show sex differences may play a role in those pathological pain conditions that are more prevalent in females, particularly, temporomandibular joint (TMJ) pain.

Alison Trinkoff, Sc.D., Professor, Department of Behavioral and Community Health, School of Nursing. Dr. Trinkoff has been studying nurses, with a special focus on two outcomes, substance use and musculoskeletal disorders. The nursing profession is about 95% female, and therefore, special issues related to working women have been an emphasis in this research. An article by Dr. Trinkoff published in the American Journal of Industrial Medicine examined the impact of work schedule and home and family demands on substance use in nurses. Motivated by concern for the health and well-being of nurses and other health care workers, the long-term goal of this work is to promote healthful working conditions that maximize the quality of patient care. Dr. Trinkoff also has experience conducting complex surveys and multivariate analyses of large data sets such as the Epidemiologic Catchment Area Program (ECA) using logistic regression, proportional hazards models, and other analytic models. This experience has led to an R01 grant award to identify risk factors for substance use among nurses (R01 DA07434). This study was framed in an occupational context, so that work organization was the overarching issue, and substance use was one outcome to be examined in relation to work organization. A second R01 was awarded in 1998, through the NIOSH NORA initiative, titled "MSD in Nurses: Organization and Physical Work Factors". The purpose of this grant is to examine the effects of organization of work on the relationship between physical job demands and musculoskeletal problems in nurses.