FEASIBILITY STUDY--IDENTIFY AND CHARACTERIZE ENDOTHELIAL INFLAMMATION GENES

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A central role for the vascular endothelium in inflammation has been appreciated for some time. However, the specific genetic programs responsible for induction and maintenance of an inflammatory state are only beginning to be identified and analyzed. An essential component of this analysis is the identification of genes which are expressed in endothelium activated by inflammatory stimuli, and which contribute to the leukocyte recruitment, morphological and biochemical changes in endothelium, and tissue damage characteristic of inflammation. This proposal details a broad approach to identifying such genes, and to identifying their possible role in inflammation. We will utilize a differential hybridization approach to identify genes which are expressed in endothelium activated by TNF-alpha, a prototypical inducer of inflammatory changes in endothelium, but which are not expressed in resting endothelium, and conversely, to identify genes whose expression is lost as a result of TNF-alpha treatment. Analysis of the function of these genes will be guided by their pattern of expression and homology to known genes and gene families. In addition, we will generate monoclonal antibodies which define activation-associated differences on the endothelial cell surface. This knowledge should provide the foundation for chemotherapeutic intervention in a broad range of inflammatory and autoimmune conditions, including rheumatoid arthritis, multiple sclerosis, atherosclerosis, and related disorders.