Characterizing Alcohol's Effects on Repair of Liver Injury

描述（由申请人提供）：大量习惯性饮酒可导致包括肝脏在内的多个组织的进行性损伤和纤维化。然而，尽管酗酒多年，许多酗酒者并没有发展成晚期肝纤维化（即肝硬化）。更适度的饮酒（每天少于2杯）实际上与某些健康益处有关，例如预防心血管疾病。然而，适度饮酒对肝脏的影响很难预测，因为有证据表明，适度饮酒可抑制某些类型肝损伤（如非酒精性脂肪性肝病- NAFLD）的纤维化进展，但会加速其他类型肝损伤（如慢性丙型肝炎- HCV）的肝硬化演变。需要研究来阐明解释肝脏对酒精的不同反应的机制。这个项目的基础假设是，饮酒会引发表观遗传事件，改变由潜在基因谱指定的肝脏修复反应。我们的具体目标是：1)确定a)晚期肝纤维化是否存在肝脏基因表达和/或表观遗传特征，b)饮酒影响这种纤维化谱；2)确定与酒精相关的纤维化谱易感性相关的基因多态性；3)确定SAMe缺乏和补充对酒精性肝硬化晚期肝纤维化患者表观遗传修饰和肝脏基因表达谱的影响。我们将利用大型的生物资源库，这些资源库保存了NAFLD、慢性HCV和酒精性肝病（ALD）患者的冷冻肝脏样本、血清/血浆、DNA和临床信息。最大和最全面的组织收集来自1000名NAFLD患者，包括相当大的非饮酒者或社交饮酒者亚群。因此，目标1和目标2的初步工作将集中在描述这些群体的肝脏基因表达、表观遗传特征和单倍型谱。平行肝脏基因表达和表观遗传学分析将在非饮酒和适度饮酒的慢性HCV患者中进行，这是我们的下一个最大的队列。由于肝活检通常不适用于ALD患者，因此分析将仅限于在肝移植时或在已经批准和资助的临床方案中获得的肝硬化ALD样本，该临床方案正在研究SAMe对肝纤维化的影响。总的来说，这些研究将提供关于酒精如何诱导表观遗传事件的新信息，这些事件调节了调节肝纤维化的基因的肝脏表达，并确定了影响这些反应的基因多态性。这些知识将有助于指导关于饮酒的风险/益处的建议，特别是对有潜在肝脏疾病的个体。鉴于社会上酒精的使用几乎无处不在，这对公共卫生具有重要影响。

DESCRIPTION (provided by applicant): Heavy habitual consumption of alcohol leads to progressive injury and fibrosis in several tissues, including the liver. However, many heavy drinkers do not develop advanced liver fibrosis (i.e., cirrhosis) despite years of alcohol abuse. More modest consumption of alcohol (< 2drinks/day) has actually been associated with certain health benefits, such as protection from cardiovascular disease. The effects of modest alcohol consumption on the liver have been difficult to predict, however, because evidence suggests that this inhibits fibrosis progression in some types of liver injury (e.g., nonalcoholic fatty liver disease - NAFLD) but accelerates the evolution of cirrhosis in others (e.g., chronic hepatitis C - HCV). Research is needed to clarify the mechanisms that account for the diverse hepatic responses to alcohol. This project is grounded in the HYPOTHESIS that alcohol consumption provokes epigenetic events that modify liver repair responses that are specified by the underlying genetic profile. Our Specific Aims are: 1) to determine if a) there are liver gene expression and/or epigenetic signatures for advanced liver fibrosis and b) alcohol consumption influences this fibrogenic profile; 2) to identify gene polymorphisms that associate with susceptibility to alcohol-related alterations in the fibrogenic profile; 3) to determine the effects of SAMe deficiency and SAMe supplementation on epigenetic modifications and the liver gene expression profile for advanced liver fibrosis in individuals with alcohol-induced cirrhosis. We will take advantage of large well-annotated bio-repositories that house frozen liver samples, serum/plasma, DNA, and clinical information from patients with NAFLD, chronic HCV, and alcoholic liver disease (ALD). The largest and most comprehensive tissue collection was obtained from > 1000 patients with NAFLD and includes sizeable sub-populations who are either non-drinkers or social drinkers. Therefore, initial work in Aims 1 & 2 will focus on characterizing the liver gene expression, epigenetic signature and haplotype profiles of these groups. Parallel liver gene expression and epigenetic analyses will be conducted in non- drinking and modest drinkers with chronic HCV, our next largest cohort. Because liver biopsies are not generally indicated in patients with ALD, analysis will be restricted to cirrhotic ALD samples that were acquired at the time of liver transplantation or during an already approved and funded clinical protocol that is investigating the effects of SAMe on liver fibrosis. In aggregate, these studies will provide novel information about how alcohol induces epigenetic events that modulate hepatic expression of genes that regulate liver fibrosis, and identify gene polymorphisms that influence these responses. Such knowledge will help to guide recommendations about the risk/benefits of alcohol use, particularly in individuals with underlying liver disease. This has important public health implications given the fact that social use of alcohol is virtually ubiquitous. PUBLIC HEALTH RELEVANCE: These studies will provide novel information about how alcohol induces epigenetic events that modulate hepatic expression of genes that regulate liver fibrosis, and identify gene polymorphisms that influence these responses. Such knowledge will help to guide recommendations about the risk/benefits of alcohol use, particularly in individuals with underlying liver disease. This has important public health implications given the fact that social use of alcohol is virtually ubiquitous.