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Molecular mechanisms of post-transplant recurrent alcoholic liver disease

移植后复发性酒精性肝病的分子机制

基本信息

批准号：
10443353
负责人：
ROTONYA M CARR
金额：
$ 34.99万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-10 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10443353
关键词：
Ablation Alcoholic Liver Diseases Alcoholic steatohepatitis Alcohols Biochemical Biogenesis Biological Assay Biological Markers Biological Models Biology Cells Ceramides Chronic Cirrhosis Closure by clamp Complex Data Development Diet Disease Early Diagnosis Early identification Energy Metabolism Enzymes Epidemiology Ethanol Experimental Models Fatty Liver Fatty acid glycerol esters Fibrosis Flow Cytometry Genetic Genetic Transcription Genetically Engineered Mouse Glucose Intolerance Goals Grant Hepatic Hepatocyte Hepatology Homeostasis Human Hyperinsulinism Impairment In Vitro Insulin Resistance Investigation Kinetics Knockout Mice Lesion Lipase Lipids Liver Liver diseases Longitudinal cohort LoxP-flanked allele Mass Spectrum Analysis Measures Mediating Metabolic Metabolic Pathway Modeling Molecular Mus Null Lymphocytes Pathway interactions Patients Physiological Physiology Prevention Protein Biosynthesis Proteins Recurrence Recurrent disease Regulation Research Research Personnel Role Serodiagnoses Serum Signal Transduction Sphingolipids Steatohepatitis Testing Therapeutic Tissues Tracer Transcriptional Regulation Translating Transplant Recipients Transplantation Triglycerides United States Up-Regulation Weight Gain Work alcohol effect alcohol prevention blood glucose regulation diagnostic biomarker dihydroceramide desaturase disorder control early detection biomarkers euglycemia global run on sequencing glucose disposal glucose tolerance hepatic gluconeogenesis improved in vivo in vivo Model insulin sensitivity insulin signaling lipidomics liver transplantation metabolic phenotype novel perilipin pharmacologic post-transplant post-transplant disease prevent problem drinker recidivism reduced food intake skills synthetic enzyme therapeutic biomarker transcription factor transcriptome sequencing

项目摘要

PROJECT SUMMARY This proposal outlines a plan to investigate the role of ceramide synthase 6 in alcohol-induced lipid droplet biogenesis and as a potential diagnostic biomarker of pre- and post-liver transplant alcoholic liver disease (ALD) recurrence. The research will use novel in vitro and in vivo model systems to investigate the hypothesis that the ceramide synthetic enzyme ceramide synthase 6 (CerS6) regulates alcohol-induced lipid droplet biogenesis through the transcriptional regulation of the lipid droplet protein, Perilipin 2 (PLIN2). Furthermore, this proposal will investigate the association between CerS6 upregulation in alcoholic steatosis and its use as an early biomarker of ALD. The researcher aims 1) to determine the mechanisms by which CerS6 regulates PLIN2 and lipid droplet biogenesis; 2) to determine the effects of hepatocyte-specific CerS6 ablation on lipid and glucose homeostasis in experimental ALD and 3) To determine if CerS6-ceramides are implicated in early pre- and post-transplant human ALD. To accomplish these Specific Aims, the researcher proposes to use genetically engineered mice and human ethanol-metabolizing VL17A cells to perform comprehensive metabolic phenotyping, lipidomics analyses, and biochemical and functional assays. In addition, the researcher aims to examine if CerS6 and its ceramide derivatives can be used to diagnose early ALD in both pre- and recurrent ALD post-transplant. Results of this project will provide evidence for targeting CerS6 as a diagnostic and therapeutic biomarker in post-transplant ALD recurrence.

项目摘要该建议概述了一项计划，以调查神经酰胺合成酶6在酒精诱导的脂滴中的作用生物起源和作为肝移植前后酒精性肝病（ALD）的潜在诊断生物标志物复发该研究将使用新的体外和体内模型系统来研究假设，神经酰胺合成酶神经酰胺合成酶6（CerS 6）调节酒精诱导的脂滴生物发生通过脂滴蛋白，周脂蛋白2（PLIN 2）的转录调节。此外，该提案将研究CerS 6在酒精性脂肪变性中的上调与其作为早期治疗药物的使用之间的关系。 ALD的生物标志物。研究人员的目标是：1）确定CerS 6调节PLIN 2的机制和脂滴生物发生; 2）确定肝细胞特异性CerS 6消融对脂质的影响 3）为了确定CerS 6-神经酰胺是否与实验性ALD中的葡萄糖稳态有关，移植前和移植后早期人类ALD。为了实现这些具体目标，研究人员建议使用基因工程小鼠和人类乙醇代谢VL 17 A细胞进行全面的代谢表型分析、脂质组学分析以及生物化学和功能测定。此外，研究人员目的是检查CerS 6及其神经酰胺衍生物是否可用于诊断前和后ALD的早期ALD。移植后ALD复发该项目的结果将为CerS 6作为诊断靶点提供证据和移植后ALD复发的治疗生物标志物。