Date

August 2009

Document Type

Dissertation

Degree Name

Ph.D.

Institution

Oregon Health & Science University

Abstract

Alcoholism/alcohol dependence is a widespread public health concern of international importance. A complex host of biological (genetic) and environmental factors interact throughout the addictive process to influence alcohol use/abuse has significantly hindered treatment and prevention of this disease. While the large genetic component of alcohol dependence is well established, the identification of specific genetic determinants has been severely limited. Physiological dependence and associated withdrawal episodes in humans constitute a powerful motivational force that contributes to relapse and perpetuates continued alcohol use/abuse despite adverse physical, social and economic consequences. Physical signs of dependence and withdrawal in mice are remarkably similar to those seen in humans, and segregate in severity among inbred strains and their derivative populations. Thus, preclinical models utilizing these genetically tractable subtypes are extremely valuable tools for the discovery and/or verification of relevant genetic sources contributing to complex human diseases like alcoholism. This dissertation presents studies focused on a region of mouse Chromosome 1 syntenic with human chromosome 1q23.2-23.3 where quantitative trait loci (QTLs) with large effects on predisposition to physical dependence and associated withdrawal severity following chronic and acute alcohol exposure (Alcdp1/Alcw1) have recently been localized to a 1.1 Mb interval. First, a systematic molecular analysis of all the genes within this interval was performed to identify the most promising candidates that may underlie the QTL effect. Seventeen candidates, with known roles in a diverse spectrum of cellular functions, were identified as high priority based on validated genotype-dependent brain expression and/or non-synonymous coding sequence variation. Second, to assist in candidate prioritization, genome-wide expression data were further analyzed for trans-regulatory effects and putative network structure. As a functional category, genes related to mitochondrial function and oxidative homeostasis appeared distinctly overrepresented both among high priority candidates residing within the QTL interval, as well as among those located elsewhere in the genome. qRT-PCR on selected genes preliminarily confirmed an interaction between the Alcdp1/Alcw1 QTL interval and a larger gene network involved in cellular stress response pathways. Damaging effects on brain mitochondrial bioenergetics and oxidative stress are some of the most well-known consequences of ethanol exposure, and is a highly plausible mechanism by which vulnerability to ethanol may be genetically influenced. Third, a biochemical approach was used to directly assess whether the mitochondrial respiratory chain exhibits genotype-dependent features before or after ethanol exposure and subsequent withdrawal. This work represents a substantial advancement toward identification of the gene(s) underlying Alcdp1/Alcw1, and suggests a promising neurobiological mechanism for its phenotypic effects. It is my sincere hope that this work will continue to improve understanding and future research directed toward identifying the specific genetic determinants of alcoholism.

Identifier

doi:10.6083/M4FF3QBN

Division

Neuroscience Graduate Program

School

School of Medicine

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