Mechanisms of In Vivo Ethanol-Induced Mitochondrial Depolarization

体内乙醇诱导线粒体去极化的机制

基本信息

批准号：
7522902
负责人：
ZHI ZHONG
金额：
$ 36.61万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7522902
关键词：
ATP phosphohydrolase Acetaldehyde Acetates Acetylcysteine Acute Address Adenine Nucleotides Affect Alcohol consumption Alcohol-Induced Disorders Alcoholic Liver Diseases Alcoholism Alcohols American Animals Antioxidants Area Arts Autophagocytosis BODIPY Binding Proteins Biochemical Bioenergetics Biological Biology Biomedical Research Blood CYP2E1 gene Cell Membrane Permeability Characteristics Chlormethiazole Chronic Consumption Cytosol Deer Mouse Dependency Detection Disease Disulfiram Dose Employee Strikes Ethanol Ethanol Metabolism Ethanol toxicity F1F0-ATP synthase FK506 Fasting Fatty Acids Fatty Liver Fatty acid glycerol esters Female Fluorescence Foundations Free Radicals Functional disorder Funding Gender Generations Goals Hepatic Hepatocyte Hepatotoxicity Histology Human Hypoxia Image Imagery Imaging Techniques Imaging technology In Vitro Individual Injury International Intervention Investigation Journals Knockout Mice Knowledge Label Laboratories Lead Life Light Lipids Liver Liver Fibrosis Liver Mitochondria Liver diseases Measurement Membrane Potentials Metabolism Methods Microscopic Microscopy Mitochondria Mitochondrial Proton-Translocating ATPases Molecular Monitor Mus National Institute on Alcohol Abuse and Alcoholism Nutritional status Optics Organelles Oxygen Paper Pathogenesis Pathway interactions Peer Review Permeability Photobleaching Pimonidazole Positioning Attribute Postdoctoral Fellow Production Productivity Protons Public Health RNA Interference Reactive Oxygen Species Recovery Reporting Research Resolution Respiration Respiratory Burst Rhodamine 123 Rodent Role Severities Sex Characteristics Slice Societies Solid Specimen Steatohepatitis System Tacrolimus Tacrolimus Binding Proteins Techniques Technology Testing Thick Time Tissues Toxicology Training Transgenic Mice Triglycerides UCP2 protein Visible Radiation Work abstracting acetaldehyde dehydrogenase alcohol abuse therapy alcohol effect alcohol exposure alcohol research alcohol response aldehyde dehydrogenase 1 aldehyde dehydrogenases base binge drinking biological research cost feeding in vivo insight knock-down lipid metabolism male methylpyrazole microsomal ethanol-oxidizing system mitochondrial dysfunction mitochondrial membrane mortality new technology novel oil red O oxidation polyphenol research study seminaphthorhodaminefluoride submicron symposium tool uptake

项目摘要

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.

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。它将填补了解酒精性肝病的一个关键空白。理由：该项目解决了对生物医学研究和公共卫生重要的问题。酒精性肝病 (ALD) 在美国影响着超过 250 万人，每年的治疗费用和生产力损失超过 15 亿美元。乙醇损害肝脏的机制尚不清楚，在开发有效的治疗方法之前，必须填补我们知识中的巨大空白。该研究的重点是利用最先进的活体多光子/共聚焦显微镜技术来了解乙醇导致活体动物线粒体功能障碍的机制，并有望填补理解 ALD 机制的关键空白。活体共焦/多光子显微镜是一项新技术，将在拟议的研究中开发和优化，作为研究活体动物细胞器和分子水平乙醇毒性的强大新工具。由于酒精生物反应的一些重要特征无法在体外系统中重现，因此此类技术至关重要。拟议项目将立即创建3个新的全职职位，其中包括2名博士后研究员和1名技术员，此外还部分支持其他两个职位。通过 ARRA 资金将创建或保留总共 3.3 个 FTE。预计这些招聘将很快从 PI 已有的候选人名单中轻松完成。详细的预算已提交并包含在该请求中。 ARRA 两年的支持结束后，调查人员将完成前 2 个具体目标。首先，他们将描述乙醇治疗后与 SIAM 和肝脂肪变性相关的体内线粒体去极化的剂量依赖性、时间过程和恢复。其次，他们将评估乙醇脱氢酶（ADH）、微粒体乙醇氧化系统（MEOS）和乙醛脱氢酶（ALDH）在乙醇诱导的线粒体去极化中的作用。 ARRA 支持的两年期间的工作将开发和应用活体多光子显微镜新技术，并为进一步研究阐明线粒体功能障碍导致 ALD 病理生理学机制奠定坚实的基础。在 ARRA 的 2 年资助期内，将向国内和国际会议提交 4-6 篇摘要，向同行评审期刊提交 2-4 篇论文。这是响应 RFA-AA-08-002（线粒体在酒精引起的组织损伤中的作用）的应用。该申请的优先级得分（179）是非资助 RFA 申请中最好的。 R01 的 RFA 支付线为 171 R21 的 RFA 支付线为 183。PI 可以解决审阅者的所有主要问题。然而，由于这是 RFA 申请，PI 不得回应批评、修改申请并重新提交。