ARACHIDONIC ACID--CYTOSKELETAL REMODELING IN EPITHELIUM

Case Western Reserve University, Cleveland OH

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Abstract

DESCRIPTION (Adapted from applicant's abstract) A comprehensive plan for Dr. Larry Alexander's development into a independent research over a 5 year period is described which builds on his background in animal physiology. The career development plan incorporates extensive practical research training and didactic course work devoted to development of a better understanding the common principles of eukaryotic membrane structure, ion transport, cellular physiology and biology. Dr. Janice Douglas who has extensive expertise in receptors and signaling will serve as the primary mentor and interact with Dr. Alexander on a day-to-day basis. She has had extensive experience as a mentor for trainees at all levels. Drs. Ulrich Hopfer and Chung-HO Chang (Department of Physiology and Division of Hypertension, respectively), will serve as a panel of mentors of the oversight committee bringing together a strong multidisciplinary group to nurture Dr. Alexander's growth into a productive research scientist. This proposal is aimed at testing the hypothesis that arachidonic acid and/or its cytochrome P450-dependent metabolites mediate cytoskeletal reorganization in kidney proximal tubular epithelial cells which may occur through the non-receptor tyrosine kinase (Src), transactivation of the EGF receptor or PI3-kinase resulting in the redistribution of apical membrane Na+/H-exchanger that provokes a decrease in proximal tubule sodium reabsorption associated with inhibition to proximal tubule Na+/H+- exchanger. Mechanical stress serves as a physiological model to mimic transient increase arterial pressure that initiates pressure natriuresis. AIM 1 determines the signal transduction pathways involved in arachidonic acid mediated cytoskeletal reorganization; AIM 2 will determine whether there is a redistribution of apical Na+/H+- exchanger (NHE3) associated with circular membrane ruffling accompanying actin reorganization and whether this provides a mechanisms for natriuresis initiated by arachidonic acid and/ or its cytochrome P450- dependent metabolites; and AIM 3 will determine whether mechanical stretch activates PLA2 and releases arachidonic acid to initiate the signaling cascade linked to apical membrane ruffling. In conclusion, every effort will be made to facilitate Larry's obtaining his ultimate career goals which are to advance up the academic ladder either in an academic health center or in the traditional university setting. With the outstanding multidisciplinary resources available at Case Western Reserve University, this represents an ideal setting for implementation of such a research scientist development award. (End of Abstract) 1 3 K01 HL04363-01 ALEXANDER