An underlying premise of the INIA-Stress consortium is that progression to abusive ethanol consumption is, at least in part, accompanied and perhaps caused by alterations in an organism's response to stress, including the stress of excessive ethanol intake/withdrawal. We propose that changes in brain gene expression networks are an important part of allostatic mechanisms leading to progressive ethanol consumption and aberrant responses to stress. We have previously used genetic and genomic approaches across brain regions of BXD recombinant inbred panel to define robust gene networks regulated by acute ethanol and relate these to ethanol behaviors, particularly regarding responses to stress. We have also identified significant overlap in expression responses to acute ethanol in mice and altered gene expression patterns seen in a primate model of excessive ethanol intake (SIP) developed by Dr. Grant, the PI of the INIA-Stress consortium. Furthermore, very recent pilot array studies in BXD mice exposed to multiple cycles of the chronic intermittent ethanol vapor (CIE) model of excessive ethanol consumption have identified remarkable homology with results from acute ethanol exposure and our data from cynomolgus macaque. Those studies have generated gene networks that allow testing initial major "hub" genes for their possible role in modifying ethanol consumption and response to stress in the CIE model. For example, we recently identified Gsk3p as an important regulator of ethanol consumption and withdrawal-induced anxiety, using AAV viral vector gene delivery studies. Based on these findings, we propose the following Organizing Hypothesis: Altered ethanol drinking and stress/endocrine phenotypes in the mouse CIE and monkey SIP models result from (and cause) adaptive responses in brain gene expression networks, resulting in a new allostatic set point.
The aims of this project will define new gene networks underlying allostatic changes in the CIE and monkey SIP models by expression profiling of CIE treatment across the BXD mouse panel and Rhesus Macaque samples of Dr. Grant (Project 1), co-analysis of results with RNA-Seq data of Dr. Williams'Project 10, and testing of candidates, including Gsk3P, using viral vector gene delivery.

Public Health Relevance

The studies proposed here can identify novel targets for future therapeutic development and contribute to our overall understanding of the neurobiology underlying the interaction between stress and ethanol during the transition to excessive ethanol consumption. Studies on one candidate gene already identified, Gsk3?, hold direct promise for future medication development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA016667-07
Application #
8426102
Study Section
Special Emphasis Panel (ZAA1-DD (51))
Program Officer
Reilly, Matthew
Project Start
2007-02-15
Project End
2017-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
7
Fiscal Year
2013
Total Cost
$235,344
Indirect Cost
$77,923
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
van der Vaart, Andrew D; Wolstenholme, Jennifer T; Smith, Maren L et al. (2016) The allostatic impact of chronic ethanol on gene expression: A genetic analysis of chronic intermittent ethanol treatment in the BXD cohort. Alcohol :
Putman, A H; Wolen, A R; Harenza, J L et al. (2016) Identification of quantitative trait loci and candidate genes for an anxiolytic-like response to ethanol in BXD recombinant inbred strains. Genes Brain Behav 15:367-81
Lopez, Marcelo F; Miles, Michael F; Williams, Robert W et al. (2016) Variable effects of chronic intermittent ethanol exposure on ethanol drinking in a genetically diverse mouse cohort. Alcohol :
Rinker, Jennifer A; Fulmer, Diana B; Trantham-Davidson, Heather et al. (2016) Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking. Alcohol :
Smith, Maren L; Lopez, Marcelo F; Archer, Kellie J et al. (2016) Time-Course Analysis of Brain Regional Expression Network Responses to Chronic Intermittent Ethanol and Withdrawal: Implications for Mechanisms Underlying Excessive Ethanol Consumption. PLoS One 11:e0146257
Cook, Melloni N; Baker, Jessica A; Heldt, Scott A et al. (2015) Identification of candidate genes that underlie the QTL on chromosome 1 that mediates genetic differences in stress-ethanol interactions. Physiol Genomics 47:308-17
Batman, Angela M; Miles, Michael F (2015) Translating Alcohol Research: Opportunities and Challenges. Alcohol Res 37:7-14
Farris, Sean P; Pietrzykowski, Andrzej Z; Miles, Michael F et al. (2015) Applying the new genomics to alcohol dependence. Alcohol 49:825-36
Hahn, Yun Kyung; Podhaizer, Elizabeth M; Farris, Sean P et al. (2015) Effects of chronic HIV-1 Tat exposure in the CNS: heightened vulnerability of males versus females to changes in cell numbers, synaptic integrity, and behavior. Brain Struct Funct 220:605-23
Padula, Audrey E; Griffin 3rd, William C; Lopez, Marcelo F et al. (2015) KCNN Genes that Encode Small-Conductance Ca2+-Activated K+ Channels Influence Alcohol and Drug Addiction. Neuropsychopharmacology 40:1928-39

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