Mechanisms of In Vivo Ethanol-Induced Mitochondrial Depolarization

摘要：该项目研究酒精如何导致线粒体功能障碍和肝脏疾病。它将填补在理解酒精性肝病方面的一个关键空白。

Summary: The project studies how alcohol causes mitochondrial dysfunction and liver disease. It will fill a critical gap in understanding alcoholic liver disease. Justification: The project addresses a problem important for biomedical research and public health. Alcoholic liver disease (ALD) affects more than 2.5 million people in the U.S. and costs over $1.5 billion/year for treatment and lost productivity. Mechanisms by which ethanol damages the liver are far from clear, and striking gaps in our knowledge must be filled before effective therapies can be developed. The study focuses on understanding the mechanisms by which ethanol causes mitochondrial dysfunction in living animals using state-of-the-art intravital multiphoton/confocal microscopy techniques and is expected to fill a critical gap in understanding the mechanisms of ALD. Intravital confocal/multiphoton microscopy is a novel technology that will be developed and optimized in the proposed study as a powerful new tool to investigate ethanol toxicity at organelle and molecular levels in living animals. Since ,some important features of the biological response to alcohol cannot be reproduced in in vitro systems, such technology is essential. The proposed project will create 3 new full-time positions immediately, including 2 postdoctoral fellows and one technician, in addition to partial support of two other positions. Total 3.3 FTEs will be created or retained through this ARRA funding. These hires are expected to be made quickly and without difficulty from a candidate list that PI already has. A detailed budget has been submitted and included with this request. At the end of two years of ARRA support, the investigators will complete the first 2 specific aims. First, they will characterize the dose-dependency, time course and recovery of mitochondrial depolarization in vivo after ethanol treatment in relation to SIAM and hepatic steatosis. Second, they will evaluate the role of alcohol dehydrogense (ADH), the microsomal ethanoloxidizing system (MEOS) and acetaldehyde dehydrogenase (ALDH) in ethanol-induced mitochondrial depolarization. The work during 2 years of ARRA support will develop and apply new technologies of intravital multiphoton microscopy and lay a solid foundation for further research to elucidate the mechanisms by which mitochondrial dysfunction contributes to the pathophysiology of ALD. During the 2-Year ARRA funding period, 4-6 abstracts will be submitted to national and international meetings and 2-4 papers will be submitted to peer-reviewed journals. This is an application in response to RFA-AA-08-002 (The Role Of Mitochondria In Alcohol-Induced Tissue Injury). The priority score of this application (179) is the best among those non-funded RFA applications. The RFA payline for R01 was 171 The RFA payline for R21 was 183. The PI can address all major concerns of the reviewers. However, because this is a RFA application, the PI is not allowed to respond to the critiques, revise the application, and resubmit.