Role of Fbxo48-mediated AMPK proteostasis in the pathogenesis and treatment of NAFLD

Fbxo48 介导的 AMPK 蛋白稳态在 NAFLD 发病机制和治疗中的作用

• 批准号: 10321596
• 负责人: Michael J. Jurczak
• 金额: $ 40.86万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321596
• 关键词: 5' -AMP-activated protein kinase; Address; Amino Acids; Animal Model; Animals; Binding; Biochemical Reaction; Catalytic Domain; Cell model; Cell physiology; Cells; Cellular biology; Chemistry; Cirrhosis; Complex; Consumption; Development; Disease; Docking; Drug Design; Experimental Models; F Box Domain; F-Box Proteins; Fibrosis; Functional disorder; Goals; Hepatic; Homology Modeling; Inflammation; Inflammatory; Insulin Resistance; Intestines; Isotopes; Knowledge; Lead; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated liver disease; Onset of illness; Orphan; Outcome; Overweight; Pathogenesis; Pathway interactions; Peptides; Pharmaceutical Preparations; Phosphorylation; Physiology; Polyubiquitination; Post-Translational Protein Processing; Pre-Clinical Model; Prevalence; Primary carcinoma of the liver cells; Principal Investigator; Process; Production; Protein Chemistry; Protein Kinase; Proteins; Research Design; Research Personnel; Rodent Model; Role; Sampling; Series; Signal Pathway; Signal Transduction; Site; Specificity; Structure; Testing; Therapeutic; Therapeutic Intervention; Ubiquitin; Ubiquitination; Work; base; chronic liver disease; design; diet-induced obesity; energy balance; extracellular vesicles; human data; inhibitor; interest; knock-down; liver biopsy; metabolic phenotype; microbial; mitochondrial metabolism; multicatalytic endopeptidase complex; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; obese person; overexpression; pre-clinical; prevent; programs; proteostasis; recruit; sensor; simple steatosis; small molecule; success; therapeutic target; ubiquitin-protein ligase

Project summary/Abstract The number of overweight and obese individuals in the U.S. has increased dramatically over the last two decades. With this rise, the prevalence of a number of obesity-associated metabolic diseases, such as type 2 diabetes (T2D) and non- alcoholic fatty liver disease (NAFLD), has similarly sky rocketed. NAFLD encompasses a range of hepatocellular alterations, including simple steatosis and steatosis with inflammation (NASH), which can lead to fibrosis, cirrhosis and hepatocellular carcinoma. Hepatic insulin resistance, changes in mitochondrial metabolism, inflammatory signaling, extracellular vesicle signaling and/or altered intestinal microbial diversity are all proposed to contribute the pathogenesis of NAFLD and NASH. However, the mechanistic basis for the pathogenesis of NAFLD remains incompletely understood and there are currently no approved treatments for NAFLD. 5'-AMP-activated protein kinase (AMPK) is a cellular energy sensor that coordinates metabolic pathways to balance energy demand with production, and growing evidence suggests that loss of AMPK activity and its downstream signaling pathways contributes to NAFLD. This proposal will test the hypothesis that increased phosphorylation-dependent, ubiquitin/proteasomal-mediated degradation of AMPK contributes to the pathogenesis of obesity-associated NAFLD. They will further establish the identity of the F-box protein that mediates the specific recognition of phosphorylated AMPK by the Skp-Cullin1-Rbx1 E3 ligase complex. Finally, studies herein will address how modulating the expression or activity of the putative F-box protein during the pathogenesis of NAFLD or after development of established NASH impacts major outcomes associated with these diseases. These goals will be achieved through a combination of approaches including cell biology, amino acid and peptide chemistry, animal physiology, metabolic isotope tracing, and homology modeling- and molecular docking-based drug design and optimization. This approach will leverage the unique and complimentary expertise of the participating investigators of this multi-principal investigator proposal, leading to new knowledge regarding the pathogenesis and a potential treatment of NAFLD.

项目概要/摘要 过去二十年来，美国超重和肥胖人数急剧增加。和 这种上升导致了许多与肥胖相关的代谢疾病的患病率，例如 2 型糖尿病 (T2D) 和非糖尿病 酒精性脂肪肝（NAFLD）的发病率也同样飙升。 NAFLD 包括一系列肝细胞疾病 改变，包括单纯性脂肪变性和炎症性脂肪变性 (NASH)，这可能导致纤维化、肝硬化和 肝细胞癌。肝脏胰岛素抵抗、线粒体代谢变化、炎症信号传导、 细胞外囊泡信号传导和/或改变的肠道微生物多样性都被认为有助于发病机制 NAFLD 和 NASH。然而，NAFLD 发病机制的机制尚不完全清楚 目前尚无批准的 NAFLD 治疗方法。 5'-AMP 激活蛋白激酶 (AMPK) 是一种细胞能量 协调代谢途径以平衡能量需求与生产的传感器，越来越多的证据表明 AMPK 活性及其下游信号通路的丧失会导致 NAFLD。该提案将测试 假设增加磷酸化依赖性、泛素/蛋白酶体介导的 AMPK 降解 肥胖相关 NAFLD 的发病机制。他们将进一步确定 F-box 蛋白的身份 介导 Skp-Cullin1-Rbx1 E3 连接酶复合物对磷酸化 AMPK 的特异性识别。最后，学习 本文将阐述如何在疾病发病机制期间调节推定的F-box蛋白的表达或活性 NAFLD 或已形成的 NASH 会影响与这些疾病相关的主要结果。这些目标 将通过细胞生物学、氨基酸和肽化学、动物 生理学、代谢同位素追踪以及基于同源建模和分子对接的药物设计和 优化。这种方法将利用参与该研究的研究人员独特且互补的专业知识。 多学科研究者的提案，带来了有关发病机制和潜在治疗方法的新知识 非酒精性脂肪性肝病。