Short-Chain Dehydrogenases in Retinol/Sterol Metabolism

视黄醇/甾醇代谢中的短链脱氢酶

• 批准号: 7809737
• 负责人: Natalia Y Kedishvili
• 金额: $ 34.14万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7809737
• 关键词: Achievement; Alabama; All-Trans-Retinol; American; Americas; Anabolism; Animal Model; Area; Award; Back; Biological Preservation; Cells; Commit; Communities; Community Outreach; Contracts; Data; Development; Diabetes Mellitus; Economics; Embryonic Development; Ensure; Enzymes; Equilibrium; Equipment; Extramural Activities; Faculty; Fatty Liver; Fetal Alcohol Syndrome; Funding; Future; Genes; Genetic Transcription; Goals; Government; Grant; Health Sciences; Health system; Historically Black Colleges and Universities; Human; Human Resources; Institution; Investments; Laboratories; Liver diseases; Maintenance; Metabolism; Modification; Mus; NADP; National Institute on Alcohol Abuse and Alcoholism; Occupations; Organ Culture Techniques; Oxidoreductase; Peer Review; Positioning Attribute; Postdoctoral Fellow; Progress Reports; Property; Proteins; Recovery; Regulation; Reporting; Research; Research Activity; Research Institute; Retinaldehyde; Retinoic Acid Receptor; Retinoids; Retinol dehydrogenase; Role; Science; Signal Transduction; Sterols; Technology; Time; Tissues; Tretinoin; United States National Institutes of Health; Universities; Xenopus; carcinogenesis; career; cofactor; cost; economic impact; enzyme activity; meetings; member; outreach program; parent grant; parent project; programs; public health relevance; response; science education

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.

描述（由申请人提供）：这是一份竞争性修订目前有效的RO1资助"视黄醇/甾醇代谢中的短链脱氢酶（SDR）"的申请，提交该申请是为了响应通知NOT-OD-09 - 058：NIH宣布恢复法案资金可用于竞争性修订申请。本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，过多或过少的视黄酸都是同样有害的，但是对负责调节视黄酸生物合成的机制仍然知之甚少。视黄酸调节超过530个基因的转录，是成年期组织分化和发育以及维持所必需的。通过视黄酸受体的异常信号传导与胎儿酒精综合征、致癌、脂肪肝和糖尿病有关。在过去几年的NIAAA的支持，我们已经确定了两组SDR酶类维生素A的活动。第一组偏好于氧化辅因子NAD+，并在细胞中将视黄醇氧化为视黄醇醛。第二组偏好还原辅因子NADPH并将视黄醇转化回视黄醇。我们提出，这两种类型的活动之间的平衡决定了稳态水平的retinaldehyde，因此，视黄酸的生物合成速率。最近，我们发现了一个以前未被认识的SDR超家族成员具有高视黄醇脱氢酶活性。我们的初步数据表明，这种酶的活性，RDH-E2S，是必不可少的视黄酸的生物合成和胚胎发育。因此，如果不考虑RDH-E2S的贡献，就不能完全实现父母补助金的目标。因此，我们建议通过包括RDH-E2S在类维生素A代谢中的性质和功能的表征来扩展母项目。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，并将通过雇用更多的工作人员刺激经济来推进《恢复法》的目标;采购额外的必要设备;并确保当前项目的可持续性和工作保留。 公共卫生相关性：《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，而美国国立卫生研究院的奖项则是通过刺激科学和健康的进步来促进经济复苏。该申请的目的是支持批准项目范围的显着扩展，以加快发现和实现研究目标的速度。我们建议扩大母基金的范围，包括一个额外的具体目标，以表征在我们的实验室中发现的一种新的酶，这可能是必不可少的维甲酸生物合成。与拟议修改相关的成本增加是由于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。这一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。伯明翰亚拉巴马大学（UAB）是亚拉巴马最大的雇主，在大学和卫生系统拥有18，000多名教职员工，并负责大学和社区内的52，900个全职等效工作。伯明翰地区每100个工作岗位中有8个，亚拉巴马每100个工作岗位中有2.8个与UAB有关。UAB在伯明翰都会区的整体经济影响每年超过30亿美元。与ARRA的目标一致，该应用程序将创造或保留5 - 6个工作岗位，并将导致对该项目目标扩展所必需的技术投资。