The goal of this proposal is to describe a carefully supervised training program that will provide me with the research skills and experience necessary to begin independent investigation. I propose to use human pulmonary endothelial cells in tissue culture as a model system to study the role of the endothelial cell in health and disease. In Phase I, a firm background in fundamental science will be provided by didactic experiences (seminars, formal course work, conferences, journal clubs and lectures) at the University of Pennsylvania and at the Wistar Institute and by an intensive laboratory experience in two settings. First, I will work with Elliot Levine, Ph.D. (at the Wistar Institute) and study the growth and function of normal cultured human endothelial cells (EC) from various sites within the pulmonary vascular tree as affected by interactions between heparin, endothelial cell growth factor, collagen, and fibronectin. We will purify and fractionate the individual components and investigate their effects on cell proliferation and metabolic functions (e.g. angiotensin converting enzyme activity). Next, I will work in the laboratory of Drs. Richard Cooper and Douglas Cines of the Hematology-Oncology Section and learn techniques with which to study EC-blood component interactions. Specifically, I will be examining the mechanisms and consequences of interactions between EC and anti-endothelial cell antibodies and immune complexes, with special attention to complement activation and platelet adherence. In Phase II, I will return to the Cardiovascular-Pulmonary Division, which has been involved in studies of the pulmonary vascular endothelium for many years, focusing on permeability and non-respiratory function and where a strong group, under the direction of Dr. R. Daniele, is dealing with the immunobiology of the lungs. There, under the supervision of my primary sponsor, Dr. Alfred P. Fishman, it will be possible to initiate studies to examine the basic nature of the processes believed to occur in diseases where direct immunologic injury to the pulmonary vasculature and diseases in which the pulmonary deposition of circulating immune complexes are thought to have prominent roles.
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