The Role of Nutrition in the Development/Progression of Alcohol-Induced Organ Injury

 描述(由申请人提供)：路易斯维尔大学酒精研究中心(ULARC)是一个区域/国家资源，旨在研究酒精引起的器官损伤的机制，并开发新的药物/干预措施来预防/治疗这种器官损伤，这两个方面都代表着重要的未得到满足的研究需求。该中心的主题在酒精中心中是独一无二的：营养的作用和酒精引起的器官损伤。这种方法具有很强的翻译性。我们的调查人员包括来自13个系和6所学院的教职员工。ULARC的具体目标是：1)促进跨学科方法，并作为研究营养和酒精引起的器官损伤的区域/国家资源； 2)提供强有力的试点项目计划和全面的教育和研究培训，以培养下一代酒精研究人员；以及3)基于ULARC的机制研究，开发潜在的酒精引起器官损伤的治疗靶点/干预措施，并将知识/干预措施转化为社区。我们将探讨营养和酒精滥用在酒精性器官功能障碍发展中的相互作用，并将评估各种潜在的营养治疗干预措施。项目(McClain/Kirpich)评估了膳食不饱和脂肪在酒精性肝病发生/发展中的作用。项目2(巴夫/冯)评估了酒精引起的肠道-肝脏轴的变化。他们研究了肠道和肝脏中的组蛋白脱乙酰酶(HDAC)在肠道屏障功能障碍和脂肪性肝炎中的作用，以及益生菌和饮食HDAC抑制剂在预防/治疗实验性ALD中的作用。项目3(Chen/Arteel)确定了母亲饮酒导致后代智力低下的机制。他们评估了酒精诱导细胞凋亡和致畸的表观遗传机制，以及通过这种机制，萝卜硫素提供表观遗传保护。项目4(Roman/Watson)评估了酒精导致急性肺损伤易感性增加的机制。他们假设，长期饮酒会触发细胞外基质重塑，导致肺组织重新铺设促炎细胞外基质，这一过程可以通过饮食干预进行调节。我们提出了三个评估营养的试点：酒精对A)肝脏、B)免疫系统和C)肠道：肝轴的相互作用，我们有一个新的“组学”核心(代谢组学/蛋白质组学)，将被所有项目和试点以及 在酒精调查员/中心外面。这些项目结合在一起，形成了一个连贯和互动的方法来研究营养和营养干预对酒精引起的器官损伤的影响。

 DESCRIPTION (provided by applicant): The University of Louisville Alcohol Research Center (ULARC) was created to serve as a regional/national resource to investigate mechanisms of alcohol induced organ injury and to develop new agents/interventions to prevent/treat this organ injury, both of which represent important unmet research needs. The theme of the center is unique among alcohol centers: the role of nutrition and alcohol-induced organ injury. The approach is highly translational. Our investigators include faculty from 13 departments and 6 colleges. The Specific Aims of the ULARC are to: 1) facilitate interdisciplinary approaches and serve as a regional/national resource for the study of nutrition and alcohol-induced organ injury; 2) provide a robust pilot project program and comprehensive education and research training in order to develop the next generation of alcohol investigators; and 3) develop potential therapeutic targets/interventions for alcohol induced organ injury based on the mechanistic research of the ULARC and translate knowledge/interventions to the community. We will explore interactions of nutrition and alcohol abuse in the development of alcohol-induced organ dysfunction, and we will evaluate diverse potential nutritional therapeutic interventions. Project (McClain/Kirpich) evaluates the role of dietary unsaturated fat in the development/progression of alcoholic liver disease. Project 2 (Barve/Feng) evaluates alcohol-induced alterations in the gut-liver axis. They study the role of histone deacetylases (HDACs) in both the intestine and liver in gut-barrier dysfunction and steatohepatitis and the role of probiotics and dietary HDAC inhibitor in preventing/treating experimental ALD. Project 3 (Chen/Arteel) determines mechanisms by which maternal alcohol consumption causes mental retardation in the offspring. They evaluate epigenetic mechanisms by which alcohol induces apoptosis and teratogenesis, and by which the nutraceutical, sulforaphane, provides epigenetic protection. Project 4 (Roman/Watson) evaluates mechanisms by which alcohol causes increased susceptibility to acute lung injury. They postulate that chronic alcohol intake triggers extracellular matrix remodeling resulting in "repavement" of lung tissue with a proinflammatory extracelluar matrix and that this process can be modulated by dietary intervention. We propose 3 pilots that evaluate nutrition:alcohol interactions on the A) liver, B) immune system, and C) the gut:liver axis, and we have a novel "omics" core (metabolomics/proteomics) that will be utilized by all projects and pilots, as well as outside alcohol investigators/centers. Together, these projects form a cohesive and interactive approach to investigate the effects of nutrition and nutritional interventions on alcohol-induced organ injury.