The monocrotaline (MCT) model of pulmonary hypertension (PH) is widely used in studies of the pathogenesis, physiology and therapy of pulmonar hypertension, both in its primary form and secondary to chronic lung disease, anorexigenic drugs and HIV. Current concepts of PH assign a primary pathogenic role to the pulmonary endothelial cell in both human PH and that induced by MCT. The overall objective of this grant is to characterize the effects of MCT on the biology of the pulmonary endothelial cell and relate them to the initiating mechanisms of PH. The applicant's overall hypothesis is that the reactive metabolite of MCT, monocrotaline pyrrole (MCTP), and its derivatives cause direct, covalent effects on pulmonary endothelial cell DNA and cytoskeletal proteins that lead to cytotoxicity, altered permeability barrier function, and cell cycle arrest and that these represent the initiating mechanisms of MCT-induced pulmonary hypertension. The applicant proposes to: 1 Characterize the interaction between MCT metabolites and macromolecules critical to endothelial cell toxicity and function. 2) Characterize the mechanisms of cytotoxicity in pulmonary endothelial cells in vivo and in vitro 3) Characterize the effects of MCTP on contractile cytoskeletal proteins essential for regulation of vascular permeability and maintenance of cell junctions; and 4) Determine the mechanisms through which MCTP induces persistent cell cycle arrest.
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