FEATURED RESEARCH

Members of the department are involved in many active research protocols. Many of these protocols are being performed on an interdepartmental basis, in conjunction with members of other clinical and basic science departments within the Medical School. The research activities in the Department of Obstetrics and Gynecology are primarily centered in six groups, with other individual faculty having active programs that contribute to the department's research mandate.

DR. CATALANO is a world-recognized expert in gestational diabetes, glucose metabolism, and insulin resistance. The research activities of his group are related to the mechanisms related to insulin resistance in pregnancy and short and long term effects on the fetus. Current grant support is focused on evaluating mechanisms related to insulin resistance in maternal skeletal muscle and adipose tissues. Biopsies are taken prior to conception and in early and late gestation and evaluated for alterations in the insulin signaling cascade as they relate to the physiological changes in glucose and lipid insulin sensitivity. Recently, they have begun evaluation of gene expression in placental tissue as a potential signal for alteration of maternal nutrients resulting in excessive fetal growth and macrosomia. They also have ongoing long-term studies evaluating infants of women with normal glucose tolerance and gestational diabetes. These children are evaluated for insulin sensitivity and body composition. The underlying hypothesis is that the altered metabolic milieu of a diabetic pregnancy increases the risk of adiposity at birth and is a long-term risk for adolescent obesity and glucose intolerance. In the clinical trial arena, they participate in the Multicenter National Study of Hyperglycemia and Adverse Perinatal Outcome (HAPO) in order to determine which values on an oral glucose tolerance test are associated with maternal and fetal perinatal morbidity. All of the above studies are currently funded through the National Institutes of Health.

DR. CLAPP is a widely-recognized expert in exercise in pregnancy; the assessment of factors involved in the regulation of fetal and placental growth; the examination of several maternal metabolic, cardiovascular and structural adaptations to pregnancy; and the assessment of that influence the changes in body composition during pregnancy and throughout infancy. He is currently involved in studies examining the effects of supine exercise during pregnancy on uterine blood flow and fetal well-being, the effects of exercise during pregnancy on immune function, and the effects of exercise during pregnancy on long-term growth and development of the offspring. Other ongoing studies involve the effects of diet during pregnancy on maternal metabolism and fetal growth and the fetal effects of cord entanglement.

DR. KIRWAN'S research interests are on the impact of strenuous physical activity on pregnancy outcome and the preventive value of diet and exercise in elderly men destined to develop type 2 diabetes mellitus. These studies are designed to examine the physiological and cellular mechanisms by which alterations in life-style factors such as exercise and nutrition can improve metabolic control and body composition in older men and women. The long-term goal is to identify new molecular targets in insulin resistance and obesity, coupled with new nutrition and exercise interventions that lead to effective treatments to delay morbidity and reduce mortality in the elderly.

Exercise training is typically associated with enhanced insulin sensitivity and is used as a first line treatment for age-related diseases such as type 2 diabetes. Results of Dr. Kirwan's work have shown that heightened insulin sensitivity is mediated by increased post-receptor insulin signaling, specifically at the distal steps of the insulin/PI 3-kinase signaling cascade that leads to GLUT-4 translocation and glucose uptake. The majority of human studies have been performed on young healthy individuals. Dr. Kirwan is currently examining whether the same holds true for elderly individuals with impaired glucose tolerance or type 2 diabetes who may have decreased protein expression.

Dr. Kirwan has also noted that while exercise generally exerts a positive effect on insulin sensitivity, it can paradoxically promote insulin resistance if it causes muscle damage. The mechanism associated with exercise induced insulin resistance appears to be related to TNF-a, which may phosphorylate specific serine residues at the level of the insulin receptor, and thus inhibit insulin signaling and glucose uptake in the muscle. Future studies will extend this work and also examine these mechanisms in elderly skeletal muscle.

Some research suggests that cardiovascular disease, type 2 diabetes, insulin resistance and obesity in later life may be explained by the "fetal origins of adult disease" hypothesis. This hypothesis proposes that maternal nutrient metabolism during pregnancy, which has a profound effect on the developing fetus, turns on genes that predispose the individual to these age-related diseases. In collaboration with Dr. Patrick Catalano, Dr. Kirwan has been examining how dietary fat intake and hormones that control growth may influence the regulation of fetal adiposity during pregnancy. These studies provide a unique opportunity to answer questions related to how maternal nutrition may alter fetal growth and contribute to the development of a phenotype that is predisposed to type 2 diabetes and obesity with advancing age.

DR. MERCER conducts research related to clinical complications of pregnancy, with a focus on prematurity. He has extensive experience in the conduct and analysis of randomized clinical trials related to prediction and prevention of preterm birth as well as prevention of infant morbidity and mortality related to prematurity. These studies involve women with prior obstetric complications and also those at risk for preterm birth in the current pregnancy. Much of this research is performed in collaboration with several multi-institutional clinical studies under the NIH-sponsored Cooperative Multicenter Network of Maternal Fetal Medicine Units.

In addition to training and sponsoring Fellows and Residents in perinatal research, Dr. Mercer is conducting research evaluating fetal pulse oximetry in labor, prevention of cerebral palsy after preterm birth, antenatal corticosteroid use before preterm birth, treatment of gestational diabetes, and prevention of preeclampsia. In 2002, Dr. Mercer and the NICHD-MFMU Network completed a trial of 17-OH progesterone administration, finding a significant reduction in preterm birth and infant morbidity when give weekly to women at high-risk.

As Associate Program Director for the CWRU-General Clinical Research Center (GCRC) at MetroHealth Medical Center, Dr. Mercer is responsible for day-to-day supervision and program development in this Center, which provides NIH-funded research support (space, beds, nursing, nutrition, equipment, lab testing) for approximately 80 research studies. These studies are conducted by investigators across almost all medical disciplines at MetroHealth. Many focus on infant and adult metabolism, exercise physiology, cardiac electrophysiology, and functional electric stimulation for rehabilitation of the spinal cord injury patient.

DR. ROSE has an active research program concerning treatment of ovarian cancer and mechanisms of resistance to chemotherapy, especially cisplatin. These interests span from clinical trials to basic laboratory research on apoptosis and molecular mechanisms of drug resistance in ovarian cancers.

Dr. Rose's clinical activity involves the care of women with Gynecologic Cancer. In an effort to improve patient outcome and provide the most recent and promising treatments. Dr. Rose is involved in numerous National Cancer Institute (Gynecologic Oncology Group) and industry sponsored trials.

The Gynecologic Oncology Research Laboratory has focused attention on the mechanisms of cisplatin resistance in epithelial ovarian cancer. Although platinum derivatives (e.g., cisplatin, carboplatin) and paclitaxel are first-line chemotherapeutic agents for the treatment of ovarian epithelial cancer, chemoresistance is a major therapeutic problem.. This pilot study involves the significance of p73 expression restoration in an intrinsically cisplatin resistant ovarian cancer cells. It is well established that p53 tumor suppressor gene expression plays a pivotal role in chemotherapy-induced apoptosis. More recently, a novel homologue of the p53 gene family, p73 has come under investigation for its role in chemotherapeutic resistance.

One potential adjunct to conventional chemotherapy is direct induction of cell death by activation of death receptor-mediated apoptosis. The death receptor ligands tumor necrosis factor (TNF), Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL) are able to induce apoptosis. More significantly, TRAIL displays minimal cytotoxicity toward normal cells and tissues in vitro and in vivo unlike the systemic administration of the Fas ligand (FasL) which resulted in acute liver failure in mice.

TRAIL a member of the TNF super family induces some cancer cells but not normal cells to undergo apoptosis. In fact, little is known of the intracellular mechanisms that control TRAIL sensitivity in epithelial ovarian cancer. In search for strategies to overcome chemoresistance we will investigate the role of p73 ectopic overexpression in mediating TRAIL induction of apoptosis.

The exact sequence of events leading to the initiation of the caspase cascade by cytochrome c release is little studied and poorly understood in intrinsically cisplatin resistant and sensitive epithelial ovarian cancer.

DR. ROTE'S group is actively investigating several clinical and basic science questions related to the Antiphospholipid Syndrome, in which women with circulating autoantibodies against phospholipids are at risk for recurrent pregnancy loss, severe and early preeclampsia, intrauterine growth restriction, prematurity, and systemic thrombosis. These clinically-relevant studies have led to an understanding of the normal cellular and molecular aspects of trophoblast differentiation and placentation in humans, particularly related to intercellular fusion of placental cytotrophoblast to form syncytiotrophoblast, the role of apoptosis in trophoblast differentiation, and mechanisms that initiate and control trophoblast differentiation.

As a result of studies on the pathophysiology of pregnancy loss, several key observations were made about normal villous trophoblast differentiation and placental growth. Differentiation results in redistribution of plasma membrane phospholipids with enrichment of the phospholipid phosphatidylserine on the syncytiotrophoblast surface. Surface PS expression is of long duration, continuing throughout pregnancy. Endogenous trophoblastic annexin A5 is externalized and binds to the phosphatidylserine-rich surface to protect the syncytiotrophoblast from formation of the clotting cascade. Antiphospholipid antibodies can cause pregnancy loss by stripping annexin A5 from the surface permitting the binding of prothrombin and coagulation.

Phosphatidylserine externalization is an essential aspect of the intertrophoblast fusion process. Intercellular fusion is necessary for the formation and expansion of the villous syncytium and development of a normal placenta. The process continues from implantation throughout the period of placental growth. Some antiphospholipid antibodies may, in fact, cause miscarriage or intrauterine growth restriction by interfering with the fusion process.

The results of another investigation of villous cytotrophoblast differentiation described the production of viral-like particles produced from all normal placentas. These viral particles originate from normal human genes that are activated in placental development. Approximately 1% of the human genome appears to be of retroviral origin, ranging from short sequences to nearly intact simple retroviral elements. These "endogenous" retroviruses are thought to have integrated early in human evolution. Despite a great deal of investigation, their purpose in human development was unknown. A small number of organs express endogenous retroviruses under physiologic conditions; the human placenta is one of these.

Two particular retroviral elements have recently been recognized as potentially important in normal villous cytotrophoblast differentiation. The normal human placental villous cytotrophoblast expresses differentiation-related transcription of the envelope regions of the retroviral-like genomes: ERV-3 and HERV-W. Dr. Rote's laboratory was the first to every describe a normal role for endogenous retroviral genes. ERV-3 envelope proteins seems to regulate much of normal trophoblast differentiation, including production of the hormone hCG. The endogenous retrovirus HERV-W appears to produce a protein that is important in villous cytotrophoblast intercellular fusion.