MEDIATORS AND EXPRESSION SYSTEMS IN RENAL INJURY

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.