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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.

项目总结