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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要酒精相关的肝病（ALD）是酒精饮用者中非常普遍的健康问题。多种的全基因组关联研究已可重复地鉴定出单个核苷酸多态性（RS738409，RS738409 c→g）在含有3（pNPLA3）基因的人类patatin样磷脂酶结构域中，这导致异亮氨酸（i）氨基酸148的甲二氨酸（M）取代，作为与宽阔的基因变体迄今为止，ALD的频谱从脂肪变性，肝炎到肝硬化。 PNPLA3是脂质液滴相关的在人肝脏中最彻底表达的蛋白质，该蛋白质已显示为甘油三酸酯脂肪酶和视网膜棕榈酸水解酶活性。但是，肝脏中PNPLA3变体的病理生理学仍然不清楚。在这个项目中，我们为人类的两个变体开发了转基因小鼠模型 PNPLA3并验证了148M小鼠模型中人ALD的关键特征。我们旨在进一步解决在酒精诱导的肝脏注射和纤维化中，148m突变的分子基础使用两者细胞和动物模型。预计该应用程序的机械投资将直接提供 1.48亿变体与相关肝脏病理学之间的因果关系的证据。总共，我们相信这个项目具有非常重要和创新性。