Epigenetic Mechanisms of Intergenerational alcohol drinking behavior.

代际饮酒行为的表观遗传机制。

• 批准号: 9360531
• 负责人: Gregory Ronald Rompala
• 金额: $ 4.4万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9360531
• 关键词: Acute; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Anti-Anxiety Agents; Attenuated; Behavior; Behavioral; Biological Assay; Cessation of life; Chromatin Structure; Chronic; Chronic stress; Corticosterone; DNA Methylation; Data; Development; Embryo; Embryonic Development; Environment; Environmental Exposure; Epigenetic Process; Ethanol; Female; Fertilization; Fostering; Gene-Modified; Generations; Genetic; Genetic Transcription; Genome; Germ Lines; Heritability; Human; Implant; Injectable; Life Stress; Mediating; Mental disorders; Metabolic stress; Modeling; Molecular; Molecular Profiling; Mothers; Mus; Neurosecretory Systems; Obesity; Oocytes; Parents; Partner in relationship; Paternal Exposure; Phenotype; Population; Prevention; Prevention strategy; Psychiatric Diagnosis; RNA; Research; Resistance; Review Literature; Risk; Risk Factors; Role; Societies; Stress; Substance abuse problem; Testing; Untranslated RNA; acute stress; alcohol behavior; alcohol exposure; alcohol risk; alcohol sensitivity; alcohol use disorder; behavior influence; behavior test; behavioral study; cost; drinking behavior; experience; experimental study; improved; insight; intergenerational; male; next generation; novel; novel strategies; offspring; preference; public health relevance; response; restraint stress; socioeconomics; sperm cell; stressor; success; trait; transmission process; treatment strategy

 DESCRIPTION (provided by applicant): Alcohol use disorder is pervasive in society, imposing enormous socioeconomic costs and contributing to tens of thousands of deaths each year. Therefore, it is critical to identify mechanisms that influence risk for alcohol use disorderto improve prevention and treatment initiatives. Our proposal is a novel approach to studying the transmission of alcohol drinking behaviors across generations. While past research has focused on genes that modify risk for alcoholism, recent evidence has demonstrated that paternal experiences can impact offspring behavior via epigenetic mechanisms in sperm. We have shown that paternal preconception alcohol exposure in mice confers decreased preference for alcohol drinking, increased sensitivity to alcohol, and blunted stress responsivity phenotypes selectively to male offspring. The current study will investigate epigenetic mechanisms that drive these intergenerational alcohol- and stress-related behaviors. One mechanism recently implicated in epigenetic inheritance is transmission of small noncoding RNAs (smRNA) from sperm to the oocyte during fertilization. Thus, the first specific aim will test the hypothesis tha chronic alcohol exposure alters expression of smRNAs in sperm. Furthermore, we will directly test the hypothesis that sperm smRNAs mediate the intergenerational impact of paternal alcohol exposure by injecting sperm smRNA from alcohol-treated mice into fertilized embryos and characterizing the alcohol- and stress- related phentoypes in resulting offspring. The second aim will examine the relationship between stress and alcohol across generations. Stress is associated with alcohol abuse in humans and whether stress can influence intergenerational alcohol drinking is unknown. Therefore, we will employ a chronic variable stress model to test the hypothesis that paternal stress impacts alcohol-related behaviors in offspring. This project is an important step in elucidating the role of epigenetic inheritance in alcohol drinking behavior These studies are important because they examine causal epigenetic mechanisms that will provide novel insight into alternative modes of inheritance beyond the genome. The findings will advance our understanding of heritable risk factors that influence alcohol abuse with major implications for the development of novel treatment and prevention strategies.

 描述（由申请人提供）：酒精使用障碍在社会中普遍存在，造成巨大的社会经济成本，每年导致数万人死亡。因此，确定影响酒精使用障碍风险的机制对于改善预防和治疗措施至关重要。我们的建议是一种新的方法来研究跨代饮酒行为的传播。虽然过去的研究主要集中在改变酗酒风险的基因上，但最近的证据表明，父亲的经历可以通过精子中的表观遗传机制影响后代的行为。我们已经表明，父亲的孕前酒精暴露在小鼠中赋予减少饮酒的偏好，增加对酒精的敏感性，并钝化压力反应表型选择性的雄性后代。目前的研究将调查驱动这些代际酒精和压力相关行为的表观遗传机制。 最近发现的表观遗传的一个机制是在受精过程中精子向卵母细胞传递小的非编码RNA（smRNA）。因此，第一个具体目标将测试慢性酒精暴露改变精子中smRNAs表达的假设。此外，我们将通过将来自酒精处理小鼠的精子smRNA注射到受精胚胎中并表征所得后代中的酒精和压力相关表型来直接检验精子smRNA介导父亲酒精暴露的代际影响的假设。第二个目标是研究几代人之间压力和酒精之间的关系。压力与人类的酒精滥用有关，压力是否会影响代际饮酒尚不清楚。因此，我们将采用一个慢性变量压力模型来检验父亲压力影响后代酒精相关行为的假设。 该项目是阐明表观遗传在饮酒行为中的作用的重要一步。这些研究很重要，因为它们研究了因果表观遗传机制，将为基因组以外的替代遗传模式提供新的见解。这些发现将促进我们对影响酒精滥用的遗传风险因素的理解，并对开发新的治疗和预防策略产生重大影响。