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Principal Investigator: Jessica Helene Hartman
Organization: MEDICAL UNIVERSITY OF SOUTH CAROLINA
Fiscal Year: 2024
Award: $354,458
Funding agency: National Institute on Alcohol Abuse and Alcoholism
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.
Terms: <4-Nitrophenol-2-Hydroxylase><Absolute ethanol><Acetaldehyde><Acute><Alcohol Chemical Class><Alcohol Drinking><Alcohol abuse><Alcohol consumption><Alcohol dehydrogenase><Alcohol toxicity><Alcohol-NAD+ Oxidoreductase><Alcohols><Ammon Horn><Brain><Brain Nervous System><Brain region><C elegans><C. elegans><C.elegans><CPE1><CYP 2E1><CYP IIE1><CYP2E><CYP2E1><CYP2E1 gene><CYPE1><CYPIIE1><Caenorhabditis elegans><Cancers><Cardiovascular Diseases><Cell Body><Cell Line><CellLine><Cells><Cerebellum><Chronic><Consumption><Cornu Ammonis><Cultured Cells><Cytochrome P-450 CYP2E1><Cytochrome P-450 IIE1><Cytochrome P-450-J><Cytochrome P450 2E1><Cytochrome P450, Family 2, Subfamily E, Polypeptide 1><Cytochrome P450, subfamily Ethanol-Inducible, Polypeptide 1><Dimethylnitrosamine N-Demethylase><Disease><Disorder><ETOH><Economic Burden><Encephalon><Endoplasmic Reticulum><Enzyme Gene><Enzymes><Ergastoplasm><EtOH abuse><EtOH drinking><EtOH use><Ethanal><Ethanol><Ethanol Metabolism><Ethanol toxicity><Ethanol-Inducible P450><Ethyl Alcohol><Exposure to><Fatty Liver><Funding Opportunities><Gene Targeting><Genotype><Goals><Grain Alcohol><Grant><Health><Heavy Drinking><Hippocampus><Human><Injury to Liver><Intake><Intermediary Metabolism><Investigators><Link><Lipid Peroxidation><Liver Steatosis><Malignant Neoplasms><Malignant Tumor><Measures><Mediating><Membrane><Metabolic><Metabolic Processes><Metabolic dysfunction><Metabolism><Methylcarbinol><Mice><Mice Mammals><Microsomes><Mitochondria><Modern Man><Murine><Mus><Muscle Disease><Muscle Disorders><Muscular Diseases><Myopathic Conditions><Myopathic Diseases and Syndromes><Myopathic disease or syndrome><Myopathy><N-Nitrosodimethylamine Demethylase><Nervous System Diseases><Nervous System Disorder><Nervous System Injuries><Nervous System Trauma><Nervous System damage><Neurologic Disorders><Neurological Damage><Neurological Disorders><Neurological Injury><Neurological trauma><Neurosciences><Organ><Organelles><Osteoporosis><Outcome><Oxidative Stress><Oxidative Stress Induction><P450-2E1><P450-J><P450C2E><Pathology><Pathway interactions><Prefrontal Cortex><Production><Regulation><Research><Research Personnel><Research Resources><Researchers><Resources><Role><Specificity><Strains Cell Lines><Stress><Subfamily Ethanol-Inducible Cytochrome P450><Subfamily IIE Cytochrome P450><System><Testing><Therapeutic><Toxic effect><Toxicities><Transgenic Mice><Transgenic Model><Transgenic Organisms><United States><Work><alcohol co-abuse><alcohol effect><alcohol exposed><alcohol exposure><alcohol ingestion><alcohol intake><alcohol metabolism><alcohol problem><alcohol product use><alcohol use><alcohol use disorder><alcoholic beverage consumption><alcoholic drink intake><binge alcohol consumption><binge drinking><cardiovascular disorder><catalase><chronic EtOH drinking><chronic alcohol consumption><chronic alcohol drinking><chronic alcohol ingestion><chronic alcohol use><chronic ethanol consumption><chronic ethanol drinking><chronic ethanol ingestion><cultured cell line><drink heavily><episodic drinking><ethanol abuse><ethanol consumption><ethanol drinking><ethanol effect><ethanol exposed><ethanol exposure><ethanol ingestion><ethanol intake><ethanol product use><ethanol use><ethanol use disorder><excessive alcohol consumption><excessive alcohol ingestion><excessive alcohol intake><excessive drinking><excessive ethanol ingestion><experiment><experimental research><experimental study><experiments><exposed to alcohol><exposed to ethanol><exposure to alcohol><exposure to ethanol><extreme drinking><frontal cortex><frontal lobe><hazardous alcohol use><heavy alcohol use><hepatic damage><hepatic injury><hepatic steatosis><hepatosteatosis><hippocampal><innovate><innovation><innovative><insight><liver damage><liver injury><malignancy><membrane structure><mitochondrial><mitochondrial dysfunction><mitochondrial metabolism><muscular disorder><neoplasm/cancer><neurological disease><neurotrauma><pathway><peroxisome><prevent><preventable death><preventable mortality><preventing><problem alcohol use><problem drinking><problematic alcohol consumption><problematic alcohol use><protein complex><respiratory><social role><sub-cellular targeting><subcellular targeting><therapeutic target><transgenic><transgenic trait>