AKR1a1 as a novel therapeutic target for Non-Alcoholic Fatty Liver Disease

AKR1a1作为非酒精性脂肪肝的新治疗靶点

基本信息

批准号：
10385931
负责人：
Nicholas Venetos
金额：
$ 5.18万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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：
2022-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10385931
关键词：
ATP Citrate (pro-S)-Lyase Ablation Acetyl-CoA Carboxylase Acute Renal Failure with Renal Papillary Necrosis Affect Amino Acids Animals Attenuated Body Weight CRISPR/Cas technology Cell Culture Techniques Cells Choline Coenzyme A Coupled Cysteine Data Diet Dietary Administration Disease Drug Targeting Enzymes Equilibrium Etiology Family Fatty Liver Fatty acid glycerol esters Functional disorder Genetic Goals Guidelines Hepatic Hepatocyte High Fat Diet Human body Impairment Incidence Intervention Isotopes Knock-out Knockout Mice Label Lipids Liver Liver diseases Mass Spectrum Analysis Mediating Modeling Modification NADP Nitric Oxide Nitric Oxide Synthase Obesity Oxidoreductase Pathogenesis Pathogenicity Pathway interactions Patients Pharmacological Treatment Pharmacology Phenotype Physiological Plant Resins Population Prevention Prevention therapy Primary carcinoma of the liver cells Protein Inhibition Protein S Proteins Public Health Regulation Resistance Risk Role S-Nitrosothiols SKIL gene Signal Transduction Site-Directed Mutagenesis Steatohepatitis Sulfhydryl Compounds Techniques Tissues Viral Wild Type Mouse diet-induced obesity dietary effective therapy genome editing in vivo inhibitor insight knock-down lipid biosynthesis lipid metabolism liver transplantation member mouse model new therapeutic target non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel prevent problem drinker protective effect restoration small molecule small molecule inhibitor therapeutic target

项目摘要

PROJECT SUMMARY/ABSTRACT Non-alcoholic Fatty Liver Disease (NAFLD) is characterized by hepatocyte fat accumulation in the absence of alcoholic or viral etiologies, and is part of a spectrum of disease ranging from isolated steatosis to hepatocellular carcinoma (HCC). NAFLD is estimated to affect nearly one-quarter of the world's population. As the incidence of NAFLD-associated HCC has risen rapidly over the past few decades, it has become clear that NAFLD is an emerging public health crisis for which there is currently no approved pharmacologic intervention. This project will investigate the role of AKR1a1—a recently discovered protein denitrosylase—in the pathogenesis of NAFLD through interrogation of its role in modulating hepatic lipid metabolism via reversible S- nitrosylation of key lipogenic enzymes. Further, the potential for AKR1a1 as a novel therapeutic target to prevent NAFLD will be investigated. To this end, the study will employ a variety of techniques including: CRISPR-Cas9 genome editing and administration of small molecule inhibitors in dietary models of murine NAFLD; isotope tracing studies to interrogate whole-pathway and enzyme-specific effects on lipid metabolism; resin-assisted capture to assess endogenous S-nitrosylation of enzymes; and site-directed mutagenesis to determine the functional role of S-nitrosylation. Together, this study will provide novel insight into the regulation of hepatic lipid metabolism and the pathophysiology of NAFLD, and identify potential therapeutic targets.

项目概要/摘要非酒精性脂肪肝（NAFLD）的特点是肝细胞脂肪在缺乏酒精的情况下堆积。酒精或病毒病因，是从孤立性脂肪变性到据估计，肝细胞癌 (HCC) 影响着世界近四分之一的人口。过去几十年来，NAFLD 相关 HCC 的发病率迅速上升，这一点已经很清楚了： NAFLD 是一种新出现的公共卫生危机，目前尚无批准的药物干预措施。该项目将研究 AKR1a1（一种最近发现的蛋白质脱亚硝基酶）在通过可逆 S- 调节肝脏脂质代谢的作用探讨 NAFLD 的发病机制此外，AKR1a1 作为新型治疗靶点的潜力。为此，该研究将采用多种技术，包括：小鼠饮食模型中的 CRISPR-Cas9 基因组编辑和小分子抑制剂的施用 NAFLD；同位素示踪研究，探讨脂质代谢的全途径和酶特异性影响；树脂辅助捕获以评估酶的内源 S-亚硝基化；以及定点诱变总之，这项研究将为调节 S-亚硝基化的功能作用提供新的见解。肝脏脂质代谢和 NAFLD 的病理生理学，并确定潜在的治疗靶点。