Exploratory Project 3 "Role of genetics in the development of chronic ethanol

探索性项目3“遗传学在慢性乙醇发展中的作用

• 批准号: 8529405
• 负责人: COLLEEN MARIE CRONIGER
• 金额: $ 2.37万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8529405
• 关键词: 1-Phosphatidylinositol 3-Kinase; A/J Mouse; Acute Alcoholic Hepatitis; Affect; Alanine Transaminase; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Animal Model; Animals; Biochemical; Body Weight; Brain; CYP2E1 gene; Choline; Chromosomes; Chromosomes, Human, 1-3; Chromosomes, Human, Pair 17; Chromosomes, Human, Pair 4; Chromosomes, Human, Pair 8; Chronic; Cirrhosis; Complication; Consomic Strain; Development; Diet; Environmental Risk Factor; Ethanol; Exhibits; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Genes; Genetic; Genetic Predisposition to Disease; Genetically Modified Animals; Genotype; Glucose; Grant; Heavy Drinking; Hepatic; Hepatocyte; Human; Hyperglycemia; Inbred Strain; Inbred Strains Mice; Ingestion; Injury; Injury to Liver; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Liquid substance; Liver; Liver diseases; Measures; Methionine; Mitochondria; Modeling; Mouse Strains; Mus; Obesity; Organ; Pathogenesis; Pathway interactions; Phenotype; Phosphorylation; Predisposition; Proteins; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Resistance; Role; Staging; Steatohepatitis; Sucrose; Testing; Triglycerides; Weight; alcohol exposure; alcohol response; chronic alcohol ingestion; cytokine; fatty acid oxidation; feeding; lipid biosynthesis; lipid transport; liver injury; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; oxidation; response

Environmental/dietary models of steatosis Genetics can contribute to alcohol intake differences in mice(15; 16), however this grant will focus on the contribution of genetics to the development of steatosis. Both genetics and environmental factors can contribute to hepatic lipogenesis and steatosis. Several dietary models of steatosis have been used. These include the high fat high sucrose (HFHS) diet, the methionine-restricted choline-deficient (MCD) and the ethanol containing diet. The mouse strain, B6 is a well-accepted model of diet-induced obesity (17). The B6 mice fed a HFHS diet for 16 weeks increase their body weight by 15% and develop fatty liver. The MCD model is a diet-induced model that affects packaging of lipid for transport and fatty acid oxidation resulting in development of macrovesicular fat in the liver (18). Chronic ingestion of ethanol using the Lieber-DeCarli ethanol liquid diet or intragastric ethanol feeding cause hepatic steatosis and hepatic injury in a variety of animal models, modeling the pathogenesis of early stages of ALD in humans (19; 20). The mechanism by which steatosis and hepatic injury develops from alcohol and diet-induced obesity is not fully understood. The purpose of this grant is to investigate the genetic susceptibility and the mechanisms for the development of steatosis and hepatic injury in novel genetic animal models, the CSS mice. We hypothesize that although the progression of steatosis to cirrhosis is similar from chronic alcohol consumption and from obesity, the genetic susceptibility to liver injury is different.

脂肪变性的环境/饮食模型遗传学可导致小鼠的酒精摄入差异（15; 16），然而，这笔赠款将集中在遗传学对脂肪变性发展的贡献。遗传学和 环境因素可导致肝脂肪生成和脂肪变性。已经使用了几种脂肪变性的饮食模型。 这些包括高脂肪高蔗糖（HFHS）饮食，蛋氨酸限制性胆碱缺乏（MCD）和乙醇 含有饮食。小鼠品系B6是饮食诱导的肥胖症的公认模型（17）。喂食HFHS饮食16周的B6小鼠体重增加了15%，并出现脂肪肝。MCD模型是一种饮食诱导的模型，其影响用于转运的脂质包装和脂肪酸氧化，导致肝脏中形成大泡脂肪（18）。在各种动物模型中，使用Lieber-DeCarli乙醇液体饮食或胃内乙醇喂养长期摄入乙醇会导致肝脂肪变性和肝损伤，从而模拟人类ALD早期阶段的发病机制（19; 20）。酒精和饮食诱导的肥胖导致脂肪变性和肝损伤的机制尚不完全清楚。这项资助的目的是研究遗传易感性和机制， 在新型遗传动物模型CSS小鼠中脂肪变性和肝损伤的发展。我们假设 虽然脂肪变性到肝硬化的进展与慢性饮酒和肥胖相似， 对肝损伤的遗传易感性是不同的。