of the application) This application seeks support for a broad program in renal research directed at understanding the cellular molecular mechanisms of renal disease. The emphasis of the program is on understanding the pathophysiologic basis of the kidney's response to acute ischemic injury. Crucial to this understanding is the fundamental knowledge of the molecular cell biological processes governing the establishment of polarity in both renal epithelial and endothelial cells, the mechanisms by which the barrier functions of both epithelium and endothelium are maintained, and the response of these tissues to the stress of acute ischemic injury. This investigation will be carried out under the aegis of four complementary and integrated projects, supported by three Core programs. The areas of focus include: 1) endothelial cell differentiation and permeability control in the renal microvasculature, as guided by the adhesion molecules ZO-1, PECAM and VE-cadherin; 2) the regulation of cortical and Golgi spectrin-actin cytoskeletal organization, and their role in establishing and maintaining Na,K-ATPase and E-cadherin polarity in renal epithelial cells; 3) the identity and role of the renal myosins, their interaction with the renal cell actin skeleton and their role in membrane trafficking and the establishment of polarity; and 4) the mechanisms establishing and maintaining tight-junctional polarity and integrity, focusing on the role of renal occludin as an adhesion molecule and its interactions with the cytoskeleton. Experiments will be carried out both in renal cell culture systems, including cultures of endothelial cells, and in established renal lines such as MDCK and LLC-PK1 cells. Renal injury in both wild type (WT) and genetically modified mice will also be studied. The core facilities, which will support this program, include a sophisticated imaging core and an in vivo renal injury core. Synergies within the group, a focus on fundamental knowledge, a planned program of external review, monthly research in progress meetings, and a robust seminar series collectively assure maximal opportunities for discovery. Understandings of significant relevance to renal disease are assured.
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