Short-Chain Dehydrogenases in Retinol/Sterol Metabolism

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DESCRIPTION (provided by applicant): This is an application for competitive revision of the currently active RO1 grant "Short-Chain Dehydrogenases (SDRs) in Retinol/Sterol Metabolism" submitted in response to the Notice NOT-OD-09-058: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. The overall goal of this project is to understand the mechanisms that regulate the steady-state levels of retinoic acid in tissues. It is well known that either too much or too little of retinoic acid is equally harmful, but the mechanisms responsible for the regulation of retinoic acid biosynthesis remain poorly understood. Retinoic acid regulates the transcription of over 530 genes and is required for differentiation and development as well as maintenance of tissues in adulthood. Abnormal signaling through retinoic acid receptors has been implicated in fetal alcohol syndrome, carcinogenesis, fatty liver disease, and diabetes. During the previous years of support from NIAAA, we have identified two groups of SDR enzymes with retinoid activities. The first group prefers the oxidative cofactor NAD+ and oxidizes retinol to retinaldehyde in the cells. The second group prefers the reductive cofactor NADPH and converts retinaldehyde back to retinol. We proposed that the balance between these two types of activities determines the steady-state levels of retinaldehyde and, therefore, the rate of retinoic acid biosynthesis. Recently, we have identified a previously unrecognized member of the SDR superfamily with high retinol dehydrogenase activity. Our preliminary data suggest that the activity of this enzyme, RDH-E2S, is essential for retinoic acid biosynthesis and embryonic development. Therefore, achievement of the goals of the parent grant will not be complete without considering the contribution of RDH-E2S. Hence, we propose to expand the parent project by including the characterization of the properties and function of RDH-E2S in retinoid metabolism. The expansion of the project is in line with the goals of ARRA, because it will accelerate the tempo of scientific research and will advance the objectives of the Recovery Act by stimulating the economy through hiring of additional staff; procuring additional needed equipment; and ensuring sustainability of the current project and job retention. PUBLIC HEALTH RELEVANCE: The purpose of the American Recovery and Reinvestment Act of 2009 is to preserve and create jobs, and for NIH awards to promote economic recovery by spurring advances in science and health. The purpose of this application is to support a significant expansion of the scope of the approved project in order to accelerate the rate of discovery and achievement of the research goals. We propose to expand the scope of the parent grant by including an additional specific aim in order to characterize a new enzyme identified in our laboratory that may be essential for retinoic acid biosynthesis. The cost increases associated with the proposed modifications result from taking advantage of a recent discovery made in our laboratory that will increase the value of the project goals and objectives. The objectives of this revision will be completed within two years and the progress reports will be submitted quarterly in order to adhere to rigorous reporting requirements. The University of Alabama at Birmingham (UAB) is Alabama's largest employer, with more than 18,000 faculty and staff at the university and in the health system, and is responsible for 52,900 full-time equivalent jobs within the university and the community. Eight in every 100 jobs in the Birmingham area, and 2.8 jobs in every 100 jobs in Alabama, are related to UAB. UAB's overall economic impact in the Birmingham metro area exceeds $3 billion annually. Consistent with ARRA goals, this application will create or retain 5-6 jobs and will result in investment in technology essential for expansion of the goals of the project.