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

• 批准号: 10621645
• 负责人: ROTONYA M CARR
• 金额: $ 23.65万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-12 至 2023-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10621645
• 关键词: Molecular; Mechanisms; Post; Transplant; Recurrent

PROJECT SUMMARY This proposal outlines a plan to investigate the role of ceramides in alcohol-induced lipid droplet biogenesis and in 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 graft loss in post-transplant recurrent 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 expression predicts graft loss in post-transplant recurrent ALD. To accomplish these Specific Aims, the researcher proposes to use CRISPR/Cas9 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 immunohistochemical expression predicts graft loss in patients with 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 这项建议概述了一项计划，以调查神经酰胺在酒精诱导的脂滴的作用， 生物发生和肝移植后酒精性肝病（ALD）复发。该研究将使用小说在 体外和体内模型系统，以研究神经酰胺合成酶神经酰胺 合成酶6（CerS 6）通过转录调节调节酒精诱导的脂滴生物发生 脂滴蛋白，磷脂酰肌醇2（PLIN 2）。此外，本提案将调查 CerS 6在酒精性脂肪变性和移植后复发性ALD的移植物丢失中的上调研究人员旨在 1)确定CerS 6调节PLIN 2和脂滴生物发生的机制; 2） 确定肝细胞特异性CerS 6消融对肝脏中脂质和葡萄糖稳态的影响， 实验ALD和3）确定CerS 6表达是否预测移植后移植物丢失 复发性ALD。 为了实现这些特定目标，研究人员建议使用CRISPR/Cas9基因 工程小鼠和人乙醇代谢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，研究人员旨在 检查CerS 6免疫组化表达是否预测了ALD术后复发患者的移植物丢失， 移植该项目的结果将为靶向CerS 6作为诊断和治疗药物提供证据 移植后ALD复发的生物标志物。