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department of pathology and laboratory medicineResearch Programs
To see a description of the Department of Pathology and Laboratory Medicine's research facilities, click here.
Research Interests
Epithelial cell proliferation and differentiation.
This research project is currently investigating a paradigm for the etiogenesis of neurodegenerative diseases. Evidence indicates unrepaired DNA purine dimers to be the molecular link between intracerebral deposition of amyloid-á protein [Aá] and neural cell loss in Alzheimer's disease. Aá reacts with the receptor for advanced glycation end products [RAGE], resulting in free radical generation that can cause oxidative DNA damages. DNA 8-8-purine dehydrodimers were therefore synthesized; one, 8-8-(2'-deoxyguanosyl)-2'-deoxyguanosine-5'-monophosphate, was used as a hapten for elicitation of rabbit anti-purine dimer antiserum. DNAs oxidized by the Fenton or from human cells reacted with chemical oxidants were recognized and bound by this antiserum. Purine dimers were formed in DNA ofcultured cells with RAGE that were exposed to Aá; these dimers were repaired. Therefore, purine dimers are formed in oxidized DNA both in vitro and in vivo. Determination of the role of DNA purine dimers in aging and neurodegenerative diseases is the central thrust of this research. Specifically, the induction and excision of DNA purine dimers are measured in cultured cells both by this immunoassay and by direct chemical techniques. The antiserum is used to measure induction and excision of purine dimers in oxidized DNA of cultured cells. These are obtained from normal individuals and from those with familial and sporadic Alzheimer's disease, Down's syndrome, and xeroderma pigmentosum. These studies can elucidate the roles of DNA purine dimers in the etiogenesis of neurodegenerative disorders. A potential benefit is development of a prospective test for identification of patients and populations at risk for neurodegeneration. These findings can be significant in neurological, gerontological, clinical, and epidemiological studies.
Immunogenetics; tumor and transplantation immunology.
Epithelial ovarian cancer is one of the leading causes of mortality in women in the United States. One of the major reasons for this is that epithelial ovarian cancers are detected only when they are at an advanced stage and have most likely metastasized. While surgical intervention aids in the removal of the primary diseased organ, chemotherapy consisting of the combination of a taxane and a platinum compound is necessitated due to spread of the tumor cells. The initial response rate is good but disease often recurs. Often ovarian tumor recurrence is accompanied by a taxol-resistant phenotype of the tumors. In addition to several different combinations of chemical and biological agents being tested for efficacy in clinical trials against such taxol refractory ovarian tumors, it is important to understand the mechanistic basis of the development of taxol resistant tumor population. Identification of cellular targets that affect the tumor cell sensitivity to anticancer drugs will eventually lead to development of new drugs or new analogs of currently utilized anticancer drugs that will directly interfere with the resistance mechanisms. Employing the mRNA differential display and the cDNA microarray technique, we identified differential expression of several genes in the taxol-resistant cells compared to their expression in the parental 2008 cells. Of particular interest to our lab was the identification of a protein involved in the G-protein coupled signal transduction pathway, called Gai1. Activation of the Gai1 protein has been shown to inhibit adenylate cyclase leading to a decrease in the activity of cAMP-dependant protein kinase A (PKA). Decrease in the PKA activity leads to activation of the mitogen-activated protein kinase (MAPK) pathway initiated by c-raf-1. Additionally, Ga subunits by virtue of their ability to bind to microtubules have been shown to modulate the microtubule polymerization dynamics. Since taxol and Gai1 have been shown to modulate the activity of c-raf1 and its downstream targets in the mitogen-activated signal transduction pathway as well as the microtubules, we investigated whether differential activation of MAPK due to Gai1 overexpression or differential binding of Gai1 with the microtubules could be associated with development of taxol resistant human ovarian carcinoma cells.
Molecular Mechanisms in Inherited Disorders of Platelet Signal Transduction. Patients with inherited platelet bleeding disorders are not uncommonly encountered in clinical practice. However, in the vast majority of these patients, the underlying molecular mechanisms leading to the platelet dysfunction are unknown. Our studies have focused on platelet signaling processes in these patients and have delineated hitherto undescribed abnormalities in key signaling proteins, including phospholipase C-beta-2, GTP binding protein G-alpha-q and protein kinase-C?theta. These studies are supported by grant awards from the NIH (NIH HL RO1 HL56724) and the March of Dimes Birth Defects Foundation. The insights from these studies will lead to better understanding of the normal platelet mechanisms and the identification of novel targets to develop newer antiplatelet agents.
Hyperglycemia, Hyperinsulinemia, and Tissue Factor Pathway of Blood Coagulation. Diabetes mellitus is well-recognized risk factor for cardiovascular disease. These patients have a high incidence of acute events including heart attacks and strokes. The impact of hyperglycemia (high blood glucose) and hyperinsulinemia (high blood insulin) on the activation of blood coagulation mechanisms has not been fully clarified. These studies, performed in collaboration with Dr. Guenther Boden, focus on the activation of the tissue factor pathway induced by hyperglycemia and hyperinsulinemia in healthy subjects and patients with diabetes mellitus. Studies to date reveal a strong evidence for the activation of tissue factor pathway by both hyperglycemia and hyperinsulinemia, with the highest levels being observed with the combination of both. Further studies will lead to an understanding of the effect of antithrombotic agents on the expression of tissue factor in diabetes mellitus. These studies are supported by a NIH- RO1 grant (RO1 DK 58895; PI: Boden; Co-PI Rao).
Impact of Antiplatelet Drugs Aspirin, Clopidogrel and Cilostazol on Platelet Function and Blood Coagulation in Patients with Peripheral Arterial Disease (PAD). Antiplatelet drugs aspirin, clopidogrel and cilostazol are widely used in the management of patients with PAD, but the effects of these agents when used in combination on platelet function and the blood coagulation system has not been clarified. Supported by a grant from Pharmaceutical industry, these studies seek to define these effects, including on the tissue factor pathway of blood coagulation. Our studies suggest that antiplatelet agents inhibit circulating levels of tissue factor, a mechanism hitherto not recognized, and which is likely to contribute to the antithrombotic effects of these agents.
Research involves the genetics of parental-origin effects (why some genes behave differently when inherited from mothers than when inherited from fathers) and on genetic factors that influence chromosome segregation (the process that ensures that each cell receives the proper type and number of chromosomes). Both of these processes depend on the interaction of specific sets of proteins with specific DNA sequences and aberrations in these interactions can lead to many diseases, including cancer. We investigate these effects in both animal models (the mouse) as well as the human population. Work is funded by the National Institutes of Health.
Research includes the laboratory evaluation of new antibiotics and chemotherapeutic agents, the evaluation of new diagnostic tests and technologies in the areas of clinical microbiology, immunology and virology, the evaluation of blood culture instruments and technologies, and the description and reporting of case presentations and reviews of new and interesting organisms and infectious diseases.
Regulation of cardiac growth and differentiation.
The faculty is well supported by funding from federal, state, and philanthropic sources. Laboratories occupy a total of 80,000 square feet of space and are furnished with state-of-the-art equipment. Core facilities available to all students include facilities for:
The Health Sciences Center houses a medical library holding current journals, medical textbook, and PCs.
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Contact Information:Department of Pathology and Laboratory Medicine Administrative Office: Clinical Labs Administrator Two Park Avenue Pavilion 3401 N. Broad Street Philadelphia, PA 19140 T: 215-707-2052 F: 215-707-2781
Graduate Program: Hemant Parekh, PhD 3400 N. Broad Street Philadelphia, PA 19140 T: 215-707-8024 F: 215-707-9413
Residency Coordinator: Room 346 Outpatient Bldg. Philadelphia, PA 19140
Teaching Office: John Wurzel, MD Course Director
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