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News and Publications
Year In Review - 2000
David J. Loskutoff, Ph.D., Chairman
iseases of the coronary and cerebral arteries account for more than half of all deaths in Western societies, and the cost of managing vascular disease in the U.S. alone is more than $100 billion annually. The growing realization that vascular cells also play a critical role in the growth of tumors and a variety of inflammatory disorders suggests that the real cost of vascular disease may be even higher. The Department of Vascular Biology applies basic principles of cell biology, chemistry and genetics to study the development, structure and diseases of the vascular system.
A common goal of the work is to define the molecular basis for the very specific interactions between vascular cells and components in the blood and the extracellular matrix. These interactions are essential for normal cell growth, movement and differentiation, and represent the most fundamental processes in biology. Department members study how the interaction between specific integrins, and proteins in the cytoplasma and extracellular matrix of cells, regulate vascular cell growth and behavior. Integrins are a family of adhesion receptors on cells, and the focal point for cell matrix-interactions. When a ligand -- an organic molecule that bonds with other molecules to form more complex structures -- binds to its integrin receptor, it sets off a signaling mechanism inside the cell and creates a chemical reaction that causes the cell to change shape, move, etc. This chemical information is carried from the extracellular matrix through the integrin receptor into the cell, and results in changes in cell structure and function. Researchers here are working to unravel the molecular details and delineate the signaling pathways that govern integrin-mediated events in vascular cells.
They also seek a more complete understanding of the various roles of complex protease cascades in the control of vascular cell function. Proteases are enzymes that can degrade and destroy other proteins, including those present in the extracellular matrix and those that form blood clots. Those currently under investigation include the plasminogen activator system, matrix metalloproteinases, and cell death (apoptosis) proteases. A single molecule of a very specific protease, for example, can activate the entire blood clotting cascade, ending with the formation of hundreds of thousands of clot-forming prothrombin molecules, an elegant and exquisitely regulated process.
On the other hand, t-PA is a protease that can dissolve clot proteins and restore normal blood flow. Raymond Schleef, Ph.D., has employed genetic engineering to introduce t-PA into leukocytes, or white blood cells, and then insert them into rats. These protease-modified leukocytes go directly to existing blood clots in the rat circulatory system and dissolve them. This may be a new and more efficient way to deliver therapeutic proteases to sites of disease and injury.
Proteases also are frequently expressed in abnormal pathological situations. For example, certain types of invasive cells, including many cancer cells, use proteases to cut through tissue barriers during metastasis. Abnormal expression of certain protease inhibitors by vascular cells may increase the risk for heart attack under certain conditions, including obesity and type II diabetes, because the proteases that normally remove pathological clots no longer function. A lack of protease inhibition, however, can lead to bleeding problems due to the premature removal of normal clots.
REGULATION OF NEW BLOOD VESSEL GROWTH
Another area of research includes investigation into the mechanisms that regulate angiogenesis, the growth of new blood vessels, with a focus on integrins and proteases/protease inhibitors. These studies provide new insights into vascular diseases including tumor angiogenesis, arteriosclerosis, stroke, thrombosis, restenosis and hypertension, and bleeding.
During the past year, several scientists in the department have achieved recognition for their innovative research efforts and have attained increasingly prominent roles in national and international symposia. In addition, funding for vascular biology research at TSRI by the National Institutes of Health continues to grow at an accelerated rate.
Two new faculty members have been recruited to the department this past year, Drs. James Quigley and Heidi Stuhlmann. Quigley, formerly a professor in the Department of Pathology at the State University of New York in Stony Brook, brings with him a longstanding interest in the biochemistry and cell biology of proteases and their inhibitors in cancer and angiogenesis. Stuhlmann, from the Mt. Sinai School of Medicine in New York, is a mouse developmental biologist interested in the early development of the vascular system. She has identified a novel gene that appears to be important for vascular development in the mouse embryo.
The past year was extremely successful in terms of scientific accomplishments, the maturation of ongoing projects, and the development of new avenues of research. The department continues to organize the Vascular Biology Lecture Series and the Vascular Biology Retreat, thus providing an informal forum for investigators at TSRI who share common interests in proteases, integrins, and vascular development and disease.
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