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: 10533324
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533324
• 关键词: 5' -AMP-activated protein kinase; Amino Acids; Animal Model; Animals; Binding; Biochemical Reaction; Catalytic Domain; Cell model; Cell physiology; Cells; Cellular biology; Chemistry; Cirrhosis; Complex; Consumption; Cullin Proteins; Development; Disease; Docking; Drug Design; Enzymes; Experimental Models; F Box Domain; F-Box Proteins; Fibrosis; Functional disorder; Goals; Hepatic; Homology Modeling; Inflammation; Inflammatory; Insulin Resistance; Intestines; Isotopes; Knowledge; Ligation; Liver; Maps; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated liver disease; 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; Proteins; Research Design; Research Personnel; Rodent Model; Role; Sampling; Series; Signal Pathway; Signal Transduction; Site; Specificity; Structure; Testing; Therapeutic; Therapeutic Intervention; Ubiquitin; Ubiquitination; Work; 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; protein degradation; 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 在过去的二十年里，美国超重和肥胖的人数急剧增加。与 这种上升，一些肥胖相关的代谢疾病的患病率，如2型糖尿病（T2 D）和非糖尿病。 酒精性脂肪肝（NAFLD）也同样飙升。NAFLD包括一系列肝细胞癌， 改变，包括单纯性脂肪变性和脂肪变性伴炎症（NASH），可导致纤维化、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， 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是致病的原因 NAFLD和NASH。然而，NAFLD发病机制的基础仍然不完全清楚 目前还没有批准的NAFLD治疗方法。5 '-AMP活化蛋白激酶（AMPK）是一种细胞能量 传感器，协调代谢途径，以平衡能源需求与生产，越来越多的证据表明， AMPK活性及其下游信号通路的丧失导致NAFLD。这项提案将考验 假设AMPK磷酸化依赖性、泛素/蛋白酶体介导的降解增加有助于 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-Cullin 1-Rbx 1 E3连接酶复合物对磷酸化AMPK的特异性识别。最后，研究 本文将阐述在疾病的发病过程中如何调节推定的F-box蛋白的表达或活性， NAFLD或已建立的NASH发展后影响与这些疾病相关的主要结局。这些目标 将通过包括细胞生物学、氨基酸和肽化学、动物 生理学、代谢同位素示踪和同源建模-以及基于分子对接的药物设计和 优化.这种方法将利用本研究参与研究者独特且互补的专业知识 多个主要研究者的建议，导致新的知识的发病机制和潜在的治疗， NAFLD。