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department of medicine

Section of hematology and thromboembolic diseases

Research Programs

 

Targeting Protease Activated Receptor 2 in Human Breast Cancer

 

Michael E. Bromberg, MD, PhD [PI]
U.S. Army Medical Research-DOD Breast Cancer Research Program. The major goal of this project to prepare retroviral vectors that will deliver small inhibitory RNA (siRNA) against PAR2 to silence PAR2 expression by human breast cancer cells and determine the effects of knocked down PAR2 expression on cell proliferation, apoptosis, TF-FVIIa complex-induced cellular signaling, cell migration, and angiogenesis.

 

 

Kininogen-Urokinase Receptor Reaction in Tumor Angiogenesis (NIH)

 

Robert W. Colman, MD [PI]
This grant will explore the anti-angiogenic effect of peptides from monoclonal antibodies to kininogens on the growth of tumors in animal models and cell culture.

 

 

Innate Immunity in Experimental Arthritis:  Role of Kininogen (NIH/NIAMS)

 

Robert W. Colman, MD [PI]

The role of the kallikrein-kinin system in experimental arthritis will be studied using monoclonal antibodies and peptides related to kininogen as well as murine knockouts of bradykinin receptors.

 

 

Kallikrein-Kinin System in Inflammatory Bowel Disease

 

Robert W. Colman, MD [PI]
Broad Foundation Medical Research Program. The major goal of this project is to study the influence of kininogen deficiency and "knockouts" of B2R and B1 R kinin receptors and tissue kallikrein in inflammatory bowel disease.

 

 

Molecular Mechanisms in Inherited Disorders of Platelet Signal Transduction (NIH and March of Dimes)

 

A. Koneti Rao, MD [PI]
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. 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 in Blood Coagulation (NIH)

 

A. Koneti Rao, MD[Co-PI; G. Boden, PI]
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.

 

 

Impact of Antiplatelet Drugs Aspirin, Clopidogrel and Cilostazol on Platelet Function and Blood Coagulation in Patients with Peripheral Arterial Disease (PAD)

 

A. Koneti Rao, MD [PI]

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 the 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.