STRESS-RELATED CHANGES IN GENE EXPRESSION AS BIOMARKERS OF RELAPSE VULNERABILITY

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): The proposed study, which will be of 2 years duration, will assess the relationship between changes in gene-expression and laboratory measures of stress-induced craving, negative emotion, and physiology previously shown to predict risk for early relapse after treatment. The long-term goal of this project is to develop novel molecular tools that can be used to predict and monitor the response to specific treatments for alcohol dependence. Preliminary studies conducted by our group have identified peripheral blood gene-expression differences between alcohol dependent subjects and social drinkers. Biological processes associated with these genes include apoptosis (programmed cell death), cell cycle regulation, and intracellular signaling cascades. Key transcription factors implicated by these gene- expression differences include HNF4-alpha, c-myc, ESR1, AR, and NF-:B. Abnormal expression of gene- networks involving these transcription factors may underlie the heightened response to stress observed in alcohol dependent subjects as well as differences in response to treatment, risk for relapse, and co-morbid disorders (e.g. depression). In the proposed study, we will recruit (n=25) treatment-seeking alcohol-dependent subjects, and (n=25) social drinkers and isolate RNA from blood collected before, immediately after, and one hour after brief guided imagery sessions involving personalized stressful or neutral-relaxing situations (one imagery condition per session) as previously described (Sinha et al., 2008). Imagery sessions will be conducted after a period of prolonged (28-day) abstinence. Gene-expression levels will be assed by microarray hybridization using Illumina Sentrix Beadchip (Human-6v2) arrays (the same platform used in our preliminary studies). Differential expression of selected genes of interested will be confirmed using Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Alcohol craving, anxiety and emotion ratings, behavioral distress responses, heart rate, blood pressure, and salivary cortisol measures will be assessed during each session. Alcoholic subjects will also be followed for 90 days after completion of the laboratory sessions to assess alcohol relapse. Specific aims include: (1) assessing whether stress imagery as compared to neutral-relaxing imagery results in differential changes in peripheral blood gene-expression;(2) assessing whether alcohol-dependent subjects and healthy controls differ in their reactivity to stress imagery as measured by induction of specific stress-related genes;and (3) determining the relationship between stress-related changes in gene-expression and physiologic and emotional responses previously shown to predict risk for relapse. As an exploratory aim we will also assess the relationship between stress-related changes in gene-expression identified in specific aims 1-3 and risk for relapse among alcohol-dependent subjects during the 90 days after testing. PUBLIC HEALTH RELEVANCE: Stress is a well known risk factor for relapse in alcohol-dependence. The goal of this project is to identify specific stress-related genes that may predict the risk for relapse in alcohol dependent subjects and allow individuals at higher-risk to be directed to more intensive treatment interventions. Better understanding of the molecular and genetic pathways mediating the effects of stress on the risk for relapse will also aid in the development of more effective treatments for dependence on alcohol and other drugs of abuse.