This proposal seeks support to establish a formal Program Project devoted to the study of mechanisms of acute and chronic renal injury. The stated goals are to be accomplished by combining in vitro with in vivo methodologies 1) to exploit the multidisciplinary strategies of molecular and cell biology, biochemistry, ultrastructure and morphometry, immunopathology and cellular immunology, and cellular, organ and whole animal physiology; and 2) to extend existing, as well as to forge new, fruitful collaborations involving investigators with diverse scientific backgrounds and interests. Project 1 studies the pathobiology of glomerular endothelial and mesangial cells in culture; Project 2 explores the role of glomerular epithelial cells in mediating glomerular sclerosis in vivo; Project 3 examines the roles of monocytes/macrophages and other mediators of acute and chronic glomerular injury in experimental nephrotic syndrome; Project 4 seeks to define the initial and subsequent events responsible for renal tubule cell injury induced by commonplace nephrotoxic drugs; Project 5 explores the pathogenetic significance of class II MHC antigen expression in renal injury; Project 6 examines the role of CD8/class I complexes in T cell function and consequent killer cell-mediated target injury; Project 7 has two major aims: 1) to further define the role of altered glomerular hemodynamic factors in the initiation and progression of glomerular sclerosis; and 2) to explore the role of elevated glomerular hydraulic pressure per se in mediating observed defects in glomerular permselectivity to macromolecules; Project 8 tests a novel hypothesis that implicates congenital reduction in total filtration surface area in the pathogenesis of systemic hypertension as well as progressive glomerular injury. A small Administrative Core is requested to provide fiscal, administrative and secretarial support for program participants. By placing this proposed program under the larger administrative structure of the recently NIH funded Harvard Center for the Study of Kidney Disease (which currently focuses only on diabetic renal disease) additional cores will not be required. Nearly all monies awarded to this program can therefore be utilized for support of the highly collaborative research projects. It is our belief that this program will foster an acceleration in the acquisition of knowledge pertaining to mechanisms of acute and chronic renal injury and thereby contribute to improved strategies for diagnosis and management of patients with renal disease.
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