Areas of Research Excellence
The research in Dr. Gorodeski's lab centers on the physiology and pathobiology of female lower reproductive tract epithelia. One major thrust of the research is epithelial transport using state-of-the-art methods to culture human normal and neoplastic vaginal, ectocervical, and endocervical cells on filters. Experiments revealed novel mechanisms and modes of transepithelial transport regulation that are unique to those epithelia. Relative to this effort, three lines of research are currently pursued: 1. Hormone regulation of the cortical act to myosin cytoskeleton, focusing on mechanisms and regulation of the resistance of the lateral intercellular space; 2. regulation of the resistance of the tight junctions, with emphasis on Occludin; 3. luminal acid secretion by vaginal cells, focusing on mechanisms and regulation of H+ and anion(s) transport and regulation of vaginal pH. The second major thrust of the research is cervical-cell apoptosis and its role in the normal growth of the cervical epithelium and the neoplastic transformation into cervical cancer. The research focuses on expression and regulation of a novel inactive P2X-receptor isoform that was recently discovered in the lab, which was found predominantly in cancer cervical epithelial cells and could play a role in the biogenesis of cervical neoplasia. A third research program was recently initiated as a collaborative effort between the University Hospitals of Cleveland, CytoCore Inc., and Dr. Gorodeski, using novel patented technology developed by the PI and UHC, which aims at improving detection and treatment of pre-malignant cervical lesions in women.
Dr. Mesiano's group investigates the physiology of human parturition with the long-term goal of developing treatment strategies to prevent preterm birth (i.e., prior to the 37th week of gestation). In the U.S. preterm birth occurs in 10-12% of all pregnancies: around 400,000 births per year. Many of these preterm babies have difficulties coping with life outside the uterus because they are born before critical organ systems have sufficiently developed. Consequently, preterm birth causes 70-80% of neonatal morbidity and is the leading cause of neonatal death. The impact of preterm birth is not limited to the neonatal period since premature babies have an increased risk of cerebral palsy, deafness, blindness, intellectual handicaps, and various cardiovascular and metabolic diseases that can extend into adult life. Clearly, preterm birth is a major public health and socioeconomic problem, and its prevention is recognized as a primary healthcare priority. Efforts to address the problem of preterm birth have been hampered by the inability to predict, prevent, or suppress preterm labor. The principal reason for this failure is that the physiology and hormonal interactions controlling the process and timing of human birth are not fully understood. Research conducted by Dr. Mesiano addresses this issue by focusing on the terminal event in the birth process: the contraction of the uterine muscle. The hormonal interactions transform the pregnant uterus from a relaxed and quiescent state to a highly contractile and excitable state required for labor and delivery is a key unsolved problem in obstetrics and gynecology. Important in this process are the principal regulators of uterine function, the steroid hormones progesterone and estrogen. Although these hormones are pivotal regulators of myometrial contractility, their roles in controlling human labor and delivery are unclear. Therefore, Dr. Mesiano and colleagues are focusing on the molecular pathways and interactions by which progesterone and estrogen determine the timing of birth.
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 blood clots. These clinically-relevant studies have led to an understanding of the normal cellular and molecular aspects of placental development 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. Dr. Rote's lab has also described the production and role of viral-like particles and proteins produced from all normal placentas. These viral particles originate from normal human genes that are activated in placental development. More than 1% of the human genome appears to be of viral origin. 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. Two particular retroviral elements have recently been recognized as potentially important in placental development: ERV-3 and HERV-W. Dr. Rote's laboratory was the first to ever describe a normal role for endogenous retroviral genes. ERV-3 envelope protein 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.
Dr. von Gruenigen's research focuses on clinical outcomes, quality of life (QOL) and lifestyle changes after the diagnosis of gynecological cancer. Dr. von Gruenigen began this work while at Northeastern Ohio Universities College of Medicine and continues to receive research support from the Stark County Community Foundation. The initial project involved a prospective study in women with early endometrial cancer who were evaluated before surgery and at six months follow up. Measures included QOL and lifestyle changes made after a diagnosis of cancer. Eighty six percent of women with endometrial cancer were overweight or obese. Minimal changes in lifestyle following a diagnosis of endometrial cancer were made at six months despite endometrial cancer being an obesity driven disease. Quality of life scores differed as a function of obesity not cancer. A second study of similar design was performed in ovarian cancer patients. However, in this group there was a statistically significant increase in complementary and alternative medicine use, and minimal changes were made in diet and exercise. In addition, this study noted decreases in physical and fatigue QOL domain scores during adjuvant chemotherapy. The National Cancer Institute (NCI) has established research priorities to define adverse patterns of weight, physical activity, and diet in their contributions to cancer, cancer prevention and control, and survivorship. In addition, cancer survivorship is a research priority at the NCI with a goal of improving health-related outcomes for cancer survivors. Single intervention trials of improved diet or increased exercise have shown that survivors with non-gynecologic malignancies who undertake positive dietary or exercise changes improve their QOL. Because endometrial cancer is the most common gynecologic cancer and most of the patients are obese with increased risk of early mortality, intervention in this group of women may increase cancer survivorship. Dr. von Gruenigen received grant funding from the Lance Armstrong Foundation to implement a research study involving overweight and obese endometrial cancer survivors. A cohort of 60 patients in remission from surgically treated early endometrial cancer is being recruited. A nutrition and lifestyle interventional program will include dietary and physical activity counseling, versus no counseling for a period of 6 months. Patients will receive physician counseling and individualized counseling by a registered dietitian. This study will use the integration of two interventions with behavioral modifications of exercise and dietary change to encourage weight loss, to improve quality of life and to decrease co-morbidities through different counseling and support techniques. In addition, their psychosocial patterns of eating will be assessed. The Gynecologic Oncology Group (GOG) has given Dr. von Gruenigen permission to retrospectively study their database in regard to clinical outcomes of obese endometrial cancer patients. Specifically, she will analyze obesity in relation to co-morbidity, recurrence and mortality.
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