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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.

项目总结