Small Molecule-Mediated Augmentation of Kidney Regeneration

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DESCRIPTION (provided by applicant): This application addresses three of the thematic areas of this RFA: 1) Applying Genomics and Other High Throughput Technologies; 2) Translating Basic Science Discoveries into New and Better Treatments; and 3) Reinvigorating the Biomedical Research Community. Our specific focus is the identification of new compounds that can accelerate the rate of renal recovery when administered post-injury to patients with acute kidney injury (AKI). Severe AKI is a common disorder with a high mortality rate. The mortality and morbidity associated with AKI resulting from ischemic, nephrotoxic or septic renal tubular injury has not decreased over the last twenty years despite renal replacement therapy. Since innate renal tubular regeneration occurs after tissue injury, there has been considerable interest in the development of treatments that enhance the regenerative capacity of the kidney when administered after induction of injury. This would be a significant advance in the field, since most therapies for AKI, which have been shown to be of use when administered prior to the onset of renal injury in experimental models, have failed to show therapeutic benefit in humans. One of the first molecular hallmarks of renal tubular regeneration in AKI is the reactivation of embryonic genes normally required during organogenesis. We therefore hypothesized that any treatment that causes expansion of these progenitor cells during embryonic development would also accelerate the rate of recovery in AKI. To test this hypothesis, we have developed a high-content screening technology to identify compounds that promote expansion of embryonic renal progenitor cells in zebrafish embryos. Using this approach we have identified a novel class of histone deacetylase inhibitors (HDACi), which caused an expansion of renal progenitor cells during embryonic renal development. Importantly, we have now shown that this novel class of HDACi increases the rate of renal recovery in a mouse model of AKI. The goal of this application is to exploit our established zebrafish screen to develop HDACi analogues that show more potent activity and lower toxicity than the first-generation compound. In addition to screening a set number of analogues from our HDACi class, we will also extend our initial screen to include libraries of compounds that contain FDA-approved drugs so that translational applications from the bench to the clinic can be expedited. Priority second-generation compounds will be subjected to target efficacy, toxicity, and post-damage regeneration potential assays in zebrafish and mouse models. Using this approach we expect to identify a number of candidate compounds with defined potential applications for use in human disease. This application is a joint venture between the University of Pittsburgh and Vanderbilt University. Studies are designed to take advantage of specific and complementary expertise of investigators at these institutions. Combinatorial chemistry, high-content screening and compound validation will be performed at the University of Pittsburgh to identify more potent HDACi analogues, and to identify synergistic compounds using our state of the art screen. Al mouse work, including target validation, toxicity assays and AKI studies will be performed at Vanderbilt University and will determine whether the second- generation compounds can accelerate the rate of recovery from AKI in mice. As this general class of agents is already being used for treatment of other human diseases, we predict that the results of these studies could be easily applied to reduce the mortality in patients with severe AKI. 2. PUBLIC HEALTH RELEVANCE: Severe acute kidney injury is common and largely reversible disorder that has a high mortality and for which there is no specific clinical treatment. Our studies have identified a new class of histone deacetylase inhibitors (HDACi) that accelerate the rate of renal recovery in a mouse model of acute kidney injury. The purpose of these studies is to identify new HDACi analogues that have a high potential for moving to clinical trials. 1.