This competing renewal application will continue to explore the role of tissue kallikrein in blood pressure regulation and in cardiovascular and renal function. Our hypothesis is that high tissue kallikrein levels have a protective role in the pathogenesis of hypertension and related diseases. Using a novel gene transfer approach, we showed that kallikrein gene delivery attenuated hypertension, cardiac hypertrophy and renal injury and inhibited neointama formation in balloon injured artery, suggesting a potential role of the tissue kallikrein-kinin system in cardiovascular and renal function. We identified a polymorphic site with 14 alleles in the transcription initiation site of the proximal promoter region of the human kallikrein gene that may serve as a powerful genetic marker for linkage analysis in hypertensive populations. These recent findings are the basis for the current application and the specific aims are as follows: 1) To develop new viral vectors harboring the human tissue kallikrein gene under the control of various promoters for long-term and high efficiency gene transfer in hypertensive rats; 2) To analyze the potential role of tissue, kallikrein in acute myocardiac ischemia and chronic heart failure following myocardial infarction in rats; 3) To analyze the potential role of tissue kallikrein for protection against renal injury 4) To analyze the potential role of tissue kallikrein in vascular cell growth and neointima formation in rat artery after balloon angioplasty, and 5) To analyze the promoter region of the human tissue kallikrein gene, and genetic linkage and association between the human kallikrein gene and hypertension in selected hypertensive populations, affected siblings, and family pedigrees. This proposed study will employ gene transfer technology as a research tool to study the role of the kallikrein-kinin system in the development of hypertension and related diseases in various animal models. Information generated from this study could provide new tools and technologies for improved detection and treatment of human hypertension, cardiovascular and renal diseases.
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