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引起线粒体功能障碍和肝病。它将填补了解酒精性肝病的关键空白。理由：该项目解决了一个对生物医学研究和公共卫生重要的问题。酒精性肝病（ALD）影响美国超过250万人，每年的治疗费用超过15亿美元，生产力降低。乙醇损害肝脏的机制远非明显，并且必须在开发有效的疗法之前填补我们所知的明显差距。该研究的重点是理解乙醇使用最先进的插入式多光子/共聚焦显微镜技术引起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。插入式共聚焦/多光子显微镜是一项新型技术，将在拟议的研究中开发和优化，作为一种强大的新工具，可以研究细胞器的乙醇毒性和活动物中的分子水平。由于在体外系统中不能再现了对酒精的生物学反应的一些重要特征，因此这种技术至关重要。拟议的项目还将立即创建3个新的全职职位，其中包括2名博士后研究员和一名技术人员，除了部分支持其他两个职位。通过此ARRA资金，将创建或保留总计3.3英尺。预计这些员工将在PI已经拥有的候选人名单中迅速且毫无困难。该请求已提交并包括了详细的预算。在ARRA支持的两年结束时，调查人员将完成前两个特定目标。首先，它们将表征乙醇处理后与暹罗和肝脂肪变性有关的剂量依赖性，时间过程和体内线粒体去极化的恢复。其次，他们将评估酒精脱水（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。在2年的ARRA支持期间，这项工作将开发和应用浸润性多光子显微镜的新技术，并为进一步的研究奠定了稳固的基础，以阐明线粒体功能障碍有助于ALD的病理生理学的机制。在2年的ARRA资金期间，将提交4-6次摘要，并将2-4篇论文提交给同行评审的期刊。这是针对RFA-AA-08-002（线粒体在酒精诱导的组织损伤中的作用）的应用。此应用程序的优先分数（179）是那些未资助的RFA应用程序中最好的。 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。但是，由于这是RFA应用程序，因此不允许PI对批评，修改应用程序并重新提交。