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: 8318718
• 负责人: COLLEEN MARIE CRONIGER
• 金额: $ 7.42万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8318718
• 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; 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 遗传学可能导致小鼠酒精摄入量的差异(15; 16），然而这笔赠款将重点关注遗传学对脂肪变性发展的贡献。无论是遗传还是 环境因素可导致肝脏脂肪生成和脂肪变性。已经使用了几种脂肪变性饮食模型。 其中包括高脂肪高蔗糖 (HFHS) 饮食、蛋氨酸限制胆碱缺乏 (MCD) 和乙醇 含有饮食。 B6 小鼠品系是一种广为接受的饮食诱导肥胖模型 (17)。饲喂 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模型，影响脂质运输和脂肪酸氧化的包装，导致肝脏中大泡脂肪的形成 (18)。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多种动物模型中的肝脂肪变性和肝损伤，从而模拟人类 ALD 早期的发病机制 (19; 20)。酒精和饮食引起的肥胖导致脂肪变性和肝损伤的机制尚不完全清楚。这笔赠款的目的是研究遗传易感性及其机制 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 尽管脂肪变性发展为肝硬化的过程与长期饮酒和肥胖相似，但 肝损伤的遗传易感性不同。