Subcellular-targeted CYP2E1 and alcohol in the brain

大脑中亚细胞靶向 CYP2E1 和酒精

基本信息

批准号：
10496067
负责人：
Jessica Helene Hartman
金额：
$ 35.45万
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：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10496067
关键词：
Acetaldehyde Acute Alcohol abuse Alcohol consumption Alcohol dehydrogenase Alcohols Brain Brain region CYP2E1 gene Caenorhabditis elegans Cardiovascular Diseases Cell Line Cells Cerebellum Chronic Consumption Cultured Cells Disease Economic Burden Endoplasmic Reticulum Enzymes Ethanol Ethanol Metabolism Ethanol toxicity Exposure to Fatty Liver Funding Opportunities Gene Targeting Genotype Goals Grant Health Heavy Drinking Hippocampus Human Intake Link Lipid Peroxidation Malignant Neoplasms Measures Mediating Membrane Metabolic Metabolic dysfunction Metabolism Microsomes Mitochondria Mus Myopathy Nervous System Trauma Neurosciences Organ Organelles Osteoporosis Outcome Oxidative Stress Oxidative Stress Induction Pathology Pathway interactions Prefrontal Cortex Production Regulation Research Research Personnel Resources Role Specificity Stress System Testing Therapeutic Toxic effect Transgenic Mice Transgenic Model Transgenic Organisms United States Work alcohol effect alcohol exposure alcohol use disorder binge drinking catalase chronic alcohol ingestion experimental study frontal lobe innovation insight liver injury mitochondrial dysfunction mitochondrial metabolism nervous system disorder peroxisome prevent preventable death protein complex respiratory subcellular targeting therapeutic target

项目摘要

PROJECT SUMMARY Metabolism of alcohol (i.e., ethanol) to acetaldehyde within different brain regions and in different subcellular compartments, and how that metabolism changes with chronic ethanol use, is not well-understood. The long- term goal is to identify adaptive changes that occur in chronic ethanol abuse and to identify therapeutic strategies to prevent or reverse neurological damage from ethanol. The objective of this proposal is to determine subcellular regulation of ethanol metabolism in mitochondria and endoplasmic reticulum (ER) by CYP2E1 during acute and chronic ethanol use, and to determine the consequences of the differential targeting. The central hypothesis is that targeting of CYP2E1 to mitochondria will be increased during chronic alcohol use in some regions of the brain that are sensitive to ethanol-induced damage, and that high mitochondrial targeting will drive high mitochondrial acetaldehyde production and resulting mitochondrial dysfunction and oxidative stress. The rationale underlying this hypothesis is that CYP2E1 expression overall is increased in brain regions that are sensitive to ethanol, including the prefrontal cortex, hippocampus, and cerebellum, and these regions also develop mitochondrial dysfunction and oxidative stress during ethanol use. The central hypothesis will be tested by pursuing three specific aims: 1) Evaluate subcellular specificity of induction of CYP2E1 by acute and chronic ethanol in the brain; 2) Determine the role of mitochondria- and ER-targeted CYP2E1 in mitochondrial effects of chronic ethanol use; and 3) Measure contribution of mitochondria- and ER- localized CYP2E1 to ethanol-induced oxidative stress. We will pursue these aims using an innovative strategy of three complementary systems: mice, C. elegans, and cultured cells. In each system we have a null background lacking CYP2E1, a wild-type CYP2E1 gene targeted to both mitochondria and ER, an ER-targeted CYP2E1, and a mitochondrial-targeted CYP2E1. The proposed research is significant because it will elucidate how ethanol metabolism by CYP2E1 changes over a chronic ethanol use paradigm, and could reveal mitochondrial CYP2E1 as a liability for ethanol toxicity. It is also significant because it generates useful platforms for studying subcellular localization-dependent effects of CYP2E1. The work will develop foundational resources that will be used by other researchers. The proximate expected outcome of this work is an understanding of how CYP2E1 contributes to the effects of ethanol in the brain during chronic and acute binge drinking. The results will have an important positive impact immediately because they will establish better understanding of the relationship between ethanol metabolism in brain regions with toxicity, and in the long-term because they lay the groundwork for identifying therapeutic opportunities.

项目概要不同脑区和不同亚细胞内酒精（即乙醇）代谢为乙醛隔室，以及新陈代谢如何随着长期使用乙醇而变化，目前尚不清楚。长- 长期目标是确定慢性酒精滥用中发生的适应性变化并确定治疗方法预防或逆转乙醇造成的神经损伤的策略。该提案的目的是确定线粒体和内质网 (ER) 中乙醇代谢的亚细胞调节 CYP2E1 在急性和慢性乙醇使用期间，并确定差异靶向的后果。核心假设是，长期饮酒期间 CYP2E1 对线粒体的靶向作用会增加在大脑的某些区域对乙醇引起的损伤敏感，并且高线粒体靶向将导致线粒体乙醛大量产生并导致线粒体功能障碍氧化应激。该假设的基本原理是 CYP2E1 表达总体在对乙醇敏感的大脑区域，包括前额皮质、海马体和小脑，以及在使用乙醇期间，这些区域还会出现线粒体功能障碍和氧化应激。中央将通过追求三个具体目标来检验假设：1）评估诱导的亚细胞特异性 CYP2E1通过大脑中的急性和慢性乙醇； 2) 确定线粒体和 ER 靶向的作用 CYP2E1 对慢性乙醇使用对线粒体的影响； 3) 测量线粒体和 ER- 的贡献将 CYP2E1 定位于乙醇诱导的氧化应激。我们将通过创新战略来实现这些目标三个互补系统：小鼠、线虫和培养细胞。在每个系统中我们都有一个 null 背景缺乏 CYP2E1，一种针对线粒体和 ER 的野生型 CYP2E1 基因，一种针对 ER 的基因 CYP2E1 和线粒体靶向 CYP2E1。拟议的研究意义重大，因为它将阐明 CYP2E1 的乙醇代谢如何改变长期乙醇使用模式，并可能揭示线粒体 CYP2E1 是乙醇毒性的责任。它也很重要，因为它产生有用的用于研究 CYP2E1 的亚细胞定位依赖性效应的平台。工作将会发展其他研究人员将使用的基础资源。这项工作的近期预期成果是了解 CYP2E1 在慢性和急性期间如何影响大脑中的乙醇酗酒。结果将立即产生重要的积极影响，因为它们将建立更好地了解大脑区域的乙醇代谢与毒性之间的关系，以及长期的，因为它们为确定治疗机会奠定了基础。