Molecular mechanisms of post-transplant recurrent alcoholic liver disease

项目总结 这项提案概述了一项研究神经酰胺合成酶6在酒精诱导的脂滴中的作用的计划。 酒精性肝病的生物发生及其作为肝移植前后潜在诊断生物标志物的研究 复发。这项研究将使用新的体外和体内模型系统来研究这一假设 神经酰胺合成酶CerS6调节酒精诱导的脂滴生物生成 通过对脂滴蛋白Perilipin 2(PLIN2)的转录调控。此外，这项建议 将调查CerS6在酒精性脂肪变性中上调与其作为早期应用之间的关系 ALD的生物标记物。研究人员的目标是：1)确定CerS6调节PLIN2的机制 和脂滴的生物发生；2)确定肝细胞特异性CerS6消融对脂质的影响 3)以确定CerS6-神经酰胺是否与ALD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 利用基因工程小鼠和人类乙醇代谢VL17A细胞进行全面的 代谢表型，脂质组学分析，生化和功能分析。此外，这位研究人员 目的是检查CerS6及其神经酰胺衍生物是否可以用于早期ALD的诊断 移植后ALD复发。该项目的结果将为将CerS6作为诊断目标提供证据 和治疗性生物标志物与ALD移植后复发的关系。

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.