Saturday, September 7, 2024
9/7/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
