The challenges and goals for the next phase of genetic research on alcohol dependence (AD) will be to i) confirm candidate genes, ii) to understand the mechanism(s) of action for individual genes in AD and iii) to use the molecular and genetic information to identify potential targets for novel interventions in AD. As a strategy to approach these complex goals, we have formulated three major organizing hypotheses that integrate and direct the individual components of this Developmental (P20) application. These include: 1. A focus on gene networks rather than individual genes which will provide mechanistic information, target identification and cross-species validation of molecular events affecting alcohol-related behaviors and risk for AD. 2. A bi-directional cross-species gene discovery and validation scheme that can provide both powerful confirmation of candidate genes and mechanistic information. Our planned studies in mice (Project 1), humans (Project 2, Pilot 2), C. elegans (Project 3), and D. melanogaster (Pilot 1) will be mutually reinforcing. 3. Initial sensitivity and acute tolerance to ethanol are phenotypes with broad cross-species experimental applicability and validated relevance to AD. For this project, for which we request four years of support, we outline a series of three developmental and two pilot projects which form a highly integrated and novel approach that implement the hypotheses outlined above. An Administrative Core and Bioinformatics Core will provide needed support across projects.
The Specific Aims of individual projects will include developmental aspects that seek to broaden our scientific base, increase integration between Center components and extend our experimental models to eventually include additional behavioral phenotypes such as acute and chronic tolerance and dependence. We expect novel contributions to the field of alcohol research from our cross-species analysis of acute ethanol effects.
|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|
|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|
|Farris, Sean P; Pietrzykowski, Andrzej Z; Miles, Michael F et al. (2015) Applying the new genomics to alcohol dependence. Alcohol 49:825-36|
|Stafford, Alexandra M; Anderson, Shawn M; Shelton, Keith L et al. (2015) Oral operant ethanol self-administration in the absence of explicit cues, food restriction, water restriction and ethanol fading in C57BL/6J mice. Psychopharmacology (Berl) 232:3783-95|
|Kendler, Kenneth S; Myers, John; Dick, Danielle (2015) The stability and predictors of peer group deviance in university students. Soc Psychiatry Psychiatr Epidemiol 50:1463-70|
|Mathies, Laura D; Blackwell, GinaMari G; Austin, Makeda K et al. (2015) SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans. Proc Natl Acad Sci U S A 112:3032-7|
|Verhulst, B; Neale, M C; Kendler, K S (2015) The heritability of alcohol use disorders: a meta-analysis of twin and adoption studies. Psychol Med 45:1061-72|
|Mamdani, Mohammed; Williamson, Vernell; McMichael, Gowon O et al. (2015) Integrating mRNA and miRNA Weighted Gene Co-Expression Networks with eQTLs in the Nucleus Accumbens of Subjects with Alcohol Dependence. PLoS One 10:e0137671|
|Sandhu, Simran; Kollah, Arnavaz P; Lewellyn, Lara et al. (2015) An inexpensive, scalable behavioral assay for measuring ethanol sedation sensitivity and rapid tolerance in Drosophila. J Vis Exp :|
Showing the most recent 10 out of 74 publications