Alcohol and tissue injury from mechanisms to treatments

 描述(申请人提供)：酒精滥用是全球发病率和死亡率的主要原因，最近的数据表明，酒精性肝病影响着1000多万美国人。除了经典公认的饮酒对肝脏的影响外，对肝脏的伤害 其他器官，如肠道、骨骼肌、肾脏、脂肪组织和神经系统，与慢性酗酒有关的发病率和死亡率也有影响。了解酒精损害细胞和器官功能的共同和组织特异性机制将导致开发合理设计的治疗干预措施，以预防和逆转长期饮酒导致的组织损伤和疾病。俄亥俄州东北酒精中心(NOAC)的总体目标是确定酒精损伤的特定分子靶点，以及了解细胞和系统对这种损伤的复杂适应性和非适应性反应，这些信息将使我们能够1)针对将减缓和/或逆转酒精诱导的器官损伤的进展的治疗干预措施，以及2)开发特定的检测方法，以评估新型治疗策略在相关临床人群中的疗效。NOAC汇聚了一支杰出的跨学科研究团队，并得到了一个管理核心、一个动物模型和细胞分离核心、一个临床核心和一个试点项目核心的支持，以及俄亥俄州东北部四个一流研究机构的杰出最先进的设施：克利夫兰诊所、凯斯西储大学/大学医院、东北俄亥俄医科大学和俄亥俄州立大学的全国儿童医院。建议了四个研究组件(RC)：RC2(Brown)调查乙醇与肠道微生物代谢物之间的相互作用和乙醇诱导的组织损伤的产生，RC2(You)询问乙醇代谢对肝细胞脂质稳态的关键调节因子Lipin-1和SIRT1的影响；RC3(Dasarathy)旨在了解慢性酒精对骨骼肌萎缩的影响，骨骼肌萎缩是酒精性肝病的关键共病特征；RC4(Nagy)研究炎症和肝细胞死亡之间的互动。NOAC的长期目标是将酒精扰乱细胞和器官功能的具体机制的新发现转化为酒精组织损伤患者的有效治疗策略。我们出色的研究团队和一流的核心设施将继续合作，解决酒精引起的组织损伤的关键机制和翻译问题，为将新发现转化为治疗策略的开发提供独特的优势，包括将酒精作用和疾病进展的分子和细胞机制转化为治疗策略。

 DESCRIPTION (provided by applicant): Alcohol abuse is a leading cause of morbidity and mortality worldwide and recent data indicate that alcoholic liver disease affects over 10 million Americans. In addition to the classically appreciated impact of alcohol use on the liver, injury to other organs, such as the intestine, skeletal muscle, kidney, adipose tissue and the neural system contribute to morbidity and mortality associated with chronic alcohol abuse. Understanding both the common and tissue-specific mechanisms by which ethanol impairs cellular and organ function will lead to the development of rationally designed therapeutic interventions to both prevent and reverse tissue damage and disease resulting from chronic alcohol consumption. The overall goal of the Northeast Ohio Alcohol Center (NOAC) is to identify specific molecular targets of ethanol-induced damage, as well as understand the complex adaptive and maladaptive responses of cells and systems to that damage, This information will enable us to 1) target therapeutic interventions that will either slow and/or reverse the progression of alcohol-induced organ injury and 2) development of specific assays that can assess the efficacy of novel therapeutic strategies in relevant clinical populations. NOAC brings together an outstanding team of interdisciplinary investigators and is supported by an Administrative Core, an Animal Models and Cell Isolation Core, a Clinical Core and a Pilot Projects Core, as well as outstanding state-of-the-art facilities at 4 premier research institution in Northeast Ohio: the Cleveland Clinic, Case Western Reserve University/University Hospitals, Northeast Ohio Medical University and Nationwide Children's Hospital at the Ohio State University. Four Research Components (RC) are proposed: RC1 (Brown) investigates the interaction between ethanol and gut microbial metabolites and the generation of ethanol-induced tissue injury, RC2 (You) interrogates the impact of ethanol metabolism in liver on lipin-1 and SIRT1, key regulators of hepatocyte lipid homeostasis; RC3 (Dasarathy) is designed to understand the impact of chronic ethanol on skeletal muscle wasting, a critical co-morbid feature of alcoholic liver disease and RC4 (Nagy) investigates the interactions between inflammation and hepatocellular death via necroptosis/apoptosis. The long-term goal of NOAC is to translate novel findings on the specific mechanisms by which ethanol disrupts cellular and organ function into effective treatment strategies for patients with alcoholic tissue injury. Our outstanding investigative team and excellent Core facilities will continue to work collaboratively to address key mechanistic and translational problems of alcohol- induced tissue injury, providing unique strengths for translating novel findings the molecular and cellular mechanisms of ethanol action and disease progression into the development of treatment strategies.