This application is submitted in response to the NIH Announcement (RFA-OD-09-003) and the proposal addresses the broad Challenge Area (08): Genomics, and the specific Challenge Topic, 08-AA-104: Regional Central Nervous System (CNS) Gene Expression. Alcohol (ethanol) abuse and dependence are substantial medical and social problems in the U.S. and constitute a significant public health concern. Alcoholism is a chronic relapsing disease, and relapse represents a major challenge to treatment efforts. Despite significant advancements in our understanding about neural substrates and environmental factors that drive this insidious cycle of addiction, few treatments are available and none have proven to be fully satisfactory in tackling this problem. Thus, a major challenge to the field is to employ preclinical models that not only facilitate advancing our knowledge about etiological factors involved in perpetuating heavy ethanol use/abuse, but also identifying new potential therapeutic targets that will be key in the development of the next generation of treatments. We have developed a mouse model of ethanol dependence and relapse drinking that is ideally suited for studies aimed at identifying molecular neurobiological events that contribute to enhanced relapse vulnerability as well as driving escalation of ethanol drinking. This research proposal is aimed at utilizing this established mouse model of ethanol dependence and relapse drinking in combination with microarray technology and informatics to profile changes in gene expression related to excessive drinking associated with ethanol dependence. A novel and innovative feature of the proposal is that it entails applying sophisticated analytical tools to facilitate identification of unique brain regional and time-dependent molecular events (mRNA abundance) related to chronic ethanol exposure, acute and protracted phases of withdrawal, and the potential for ethanol consumption to impact these changes. Thus, this comprehensive experimental approach will generate a very rich data set indicating changes in gene expression that are unique to each of these aspects of the model as well as transcriptional alterations in pathways/functions that are common across time points and brain regions. This highly unique data set will, in turn, not only provide new and valuable insights about mechanisms relevant to the problem of dependence and harmful drinking, but also provide a valuable resource to the field in revealing potential new and novel therapeutic targets that may be especially informative for efforts to develop more effective treatments for this major medical and social problem, namely alcohol abuse and alcoholism.
This project aims to identify genetic and molecular neuroadaptive events related to excessive drinking associated, with alcohol dependence with the hope of revealing potential new and novel therapeutic targets for development of new treatments for alcoholism.
| 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 |
| Cui, Changhai; Noronha, Antonio; Warren, Kenneth R et al. (2015) Brain pathways to recovery from alcohol dependence. Alcohol 49:435-52 |
| Melendez, Roberto I; McGinty, Jacqueline F; Kalivas, Peter W et al. (2012) Brain region-specific gene expression changes after chronic intermittent ethanol exposure and early withdrawal in C57BL/6J mice. Addict Biol 17:351-64 |
