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.

项目摘要/摘要非酒精性脂肪肝疾病（NAFLD）的特征是在没有肝细胞脂肪的情况下积累酒精性或病毒病因，是一系列疾病的一部分，从孤立的脂肪变性到肝细胞癌（HCC）。据估计，NAFLD会影响世界人口中几乎四分之一。作为在过去的几十年中，与NAFLD相关的HCC的事件迅速上升，很明显 NAFLD是一种新兴的公共卫生危机，目前尚无批准的药物结肠干预。该项目将研究AKR1A1（最近发现的蛋白脱硝基酶）在 NAFLD通过询问其在通过可逆S-调节肝脂质代谢中的作用来使其发病关键脂肪酶的硝基化。此外，AKR1A1作为一种新型治疗靶点的潜力将调查防止NAFLD。为此，该研究将采用各种技术，包括：在鼠饮食模型中，CRISPR-CAS9基因组编辑和小分子抑制剂的给药 nafld;同位素追踪研究，以询问全途径和酶特异性对脂质代谢的影响；树脂辅助捕获以评估酶的内源性S-硝基化；和定向的诱变确定S-亚硝基化的功能作用。这项研究将共同提供有关调节的新见解肝脂质代谢和NAFLD的病理生理学，并确定潜在的治疗靶点。