The pathophysiological function of PNPLA3-148M variant in alcohol-induced liver injury

PNPLA3-148M变异在酒精性肝损伤中的病理生理作用

• 批准号: 10366395
• 负责人: X Charlie Dong
• 金额: $ 46.02万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366395
• 关键词: Address; Alcohol consumption; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcohols; Amino Acids; Animal Model; Biochemical; Cell Culture Techniques; Cell Death; Cell model; Cirrhosis; Data; Development; Disease; Fatty Liver; Fibrosis; Functional disorder; Future; Genes; Health; Hepatic; Hepatic Stellate Cell; Hepatitis; Human; Hydrolase; In Vitro; Individual; Investigation; Isoleucine; Knowledge; Kupffer Cells; Life; Lipase; Lipids; Liver; Liver Fibrosis; Liver diseases; Mediating; Mediation; Metabolism; Methionine; Mission; Molecular; Mutation; NF-kappa B; Pathogenesis; Pathology; Pathway interactions; Patients; Phenocopy; Phospholipase; Physiological; Play; Prevention; Primary carcinoma of the liver cells; Process; Proteins; Public Health; Regulation; Research; Role; Signal Pathway; Single Nucleotide Polymorphism; Source; TNF gene; Transforming Growth Factor beta; Transgenic Mice; United States National Institutes of Health; Validation; Variant; burden of illness; common treatment; expectation; fibrogenesis; gain of function; genetic variant; genome wide association study; high risk; in vivo; innovation; insight; liver inflammation; loss of function; macrophage; migration; mouse model; mutant; new therapeutic target; novel; response; retinyl palmitate; risk variant; therapeutic development

Project Summary Alcohol-related liver disease (ALD) is a very common health problem among alcohol drinkers. Multiple genome-wide association studies have reproducibly identified a single nucleotide polymorphism (rs738409, C→G) in the human patatin-like phospholipase domain containing 3 (PNPLA3) gene, which results in isoleucine (I) to methionine (M) substitution at amino acid 148, as the most significant gene variant associated with a broad spectrum of ALD ranging from steatosis, hepatitis, to cirrhosis to date. PNPLA3 is a lipid droplet-associated protein that is most abundantly expressed in human liver, which has been shown to have triglyceride lipase and retinyl palmitate hydrolase activities. However, the pathophysiology of the 148M variant of PNPLA3 in the liver remains largely unclear. In this project, we have developed transgenic mouse models for both variants of human PNPLA3 and validated the key features of human ALD in the 148M mouse model. We aim to further address the molecular underpinning of the 148M mutation in the alcohol-induced hepatic inflammation and fibrosis using both cell and animal models. It is expected that the mechanistic investigation in this application will provide direct evidence of the causal relationship between the 148M variant and the associated liver pathology. Altogether, we believe that this project is highly significant and innovative.

项目概要 酒精相关性肝病（ALD）是饮酒者中非常常见的健康问题。多种的 全基因组关联研究可重复地鉴定出单核苷酸多态性（rs738409， C→G) 位于含有 3 (PNPLA3) 基因的人 patatin 样磷脂酶结构域中，产生异亮氨酸 (I) 在氨基酸 148 处替换为蛋氨酸 (M)，作为与广泛相关的最重要的基因变异 迄今为止，ALD 的范围从脂肪变性、肝炎到肝硬化。 PNPLA3 是一种脂滴相关蛋白 在人类肝脏中表达最丰富的蛋白质，已被证明具有甘油三酯脂肪酶和 视黄醇棕榈酸酯水解酶活性。然而，PNPLA3 148M 变体在肝脏中的病理生理学 很大程度上仍不清楚。在这个项目中，我们开发了针对人类两种变体的转基因小鼠模型 PNPLA3 并在 148M 小鼠模型中验证了人类 ALD 的关键特征。我们的目标是进一步解决 使用两者研究酒精诱导的肝脏炎症和纤维化中 148M 突变的分子基础 细胞和动物模型。预计本申请中的机制研究将提供直接的帮助 148M 变异与相关肝脏病理之间因果关系的证据。总而言之，我们 相信该项目具有非常重大的意义和创新性。