Short-Chain Dehydrogenases in Retinol/Sterol Metabolism

描述(由申请人提供)：这是针对NOT-OD-09-058：美国国立卫生研究院宣布恢复法资金可用于竞争性修订申请的通知NOT-OD-09-058提交的对目前有效的RO1拨款“视黄醇/甾醇代谢中的短链脱氢酶(SDR)”的竞争性修订申请。这个项目的总体目标是了解调节组织中维甲酸稳态水平的机制。众所周知，太多或太少的维甲酸都是有害的，但调节维甲酸生物合成的机制仍然知之甚少。维甲酸调节超过530个基因的转录，是成年后组织分化、发育和维持所必需的。维甲酸受体的异常信号与胎儿酒精综合征、癌症、脂肪肝和糖尿病有关。在前几年NIAAA的支持下，我们已经鉴定出两组具有维甲酸活性的SDR酶。第一组偏爱氧化辅因子NAD+，并在细胞内将视黄醇氧化为视黄醛。第二组偏爱还原辅因子NADPH，并将视黄醛转化回视黄醇。我们认为，这两种活性之间的平衡决定了维甲醛的稳态水平，从而决定了维甲酸的生物合成速度。最近，我们发现了SDR超家族中一个先前未被发现的成员，它具有很高的视黄醇脱氢酶活性。我们的初步数据表明，这种酶的活性，RDH-E2S，是维甲酸生物合成和胚胎发育所必需的。因此，如果不考虑RDH-E2S的贡献，父赠款目标的实现将是不完整的。因此，我们建议扩展父项目，包括RDH-E2S在类维A酸代谢中的性质和功能的表征。该项目的扩大符合ARRA的目标，因为它将加快科学研究的步伐，并将通过雇用更多工作人员来刺激经济、采购更多所需设备以及确保当前项目的可持续性和保住工作，从而推进恢复法的目标。 与公共健康相关：2009年《美国复苏和再投资法案》的目的是保护和创造就业机会，并向NIH颁发奖项，以通过刺激科学和卫生领域的进步来促进经济复苏。这项申请的目的是支持大幅扩大核准项目的范围，以加快发现和实现研究目标的速度。我们建议扩大父母资助的范围，包括一个额外的特定目标，以便鉴定我们实验室鉴定的一种可能对维甲酸生物合成至关重要的新酶。与拟议的修改相关的成本增加是因为利用了我们实验室最近的一项发现，这将增加项目目标和目的的价值。这次修订的目标将在两年内完成，进度报告将每季度提交一次，以遵守严格的报告要求。阿拉巴马大学伯明翰分校(UAB)是阿拉巴马州最大的雇主，在该大学和医疗系统拥有超过1.8万名教职员工，负责该大学和社区内52,900个相当于全职工作的工作。伯明翰地区每100个工作岗位中有8个与UAB有关，阿拉巴马州每100个工作岗位中有2.8个工作岗位与UAB有关。UAB对伯明翰大都市区的整体经济影响每年超过30亿美元。与ARRA的目标一致，这项申请将创造或保留5-6个就业机会，并将导致对扩大项目目标所必需的技术的投资。

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.