Finegersh, Andrey
(2014)
Epigenetic Effects of Ethanol.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Alcohol use disorder (AUD) is prevalent and associated with significant mortality and socioeconomic costs globally. Despite the tremendous burden of AUD, mechanisms of alcohol (ethanol) action that underlie the development of AUD are still not known. This dissertation addresses the role of epigenetic modifications in heritability of AUD and mechanisms of ethanol by testing three distinct hypotheses: 1) paternal ethanol exposure regulates ethanol drinking and ethanol-related behavior in offspring; 2) acute ethanol induces conserved changes to histone modifications at model gene promoters in the cerebral cortex; 3) chronic intermittent vapor ethanol and withdrawal induce dynamic changes in gene regulation via discrete histone modifications in accumbal dopamine 1 receptor positive medium spiny neurons. To test these hypotheses, this dissertation developed new models for studying heritability of ethanol drinking using paternal vapor ethanol exposure and epigenetic modifications in a neuronal subtype using fluorescence activated cell sorting. The results presented in this thesis provide evidence for epigenetic effects of ethanol in mediating heritability of ethanol drinking and sensitivity to ethanol selectively in male offspring as well as ethanol-induced gene regulation in the cerebral cortex. Additionally, they set up future studies of ethanol’s epigenetic mechanisms in neuronal subtypes, which will increase sensitivity of current assays to detect cell-specific changes in gene regulation. These results are expected to have important implications for the development of drugs that target epigenetic modifying enzymes for treatment of AUD.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
28 July 2014 |
| Date Type: |
Publication |
| Defense Date: |
15 July 2014 |
| Approval Date: |
28 July 2014 |
| Submission Date: |
25 July 2014 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
148 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Pharmacology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
ethanol, alcoholism, epigenetics, chromatin, histones, dna methylation, heritability, dopamine, fluorescence activated cell sorting, gene expression, transgenerational inheritance |
| Date Deposited: |
28 Jul 2014 13:09 |
| Last Modified: |
19 Dec 2016 14:42 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/22521 |
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