Targeting Shc to reduce inflammation and fibrosis in the aging liver

以 Shc 为靶点，减少衰老肝脏的炎症和纤维化

基本信息

批准号：
10213634
负责人：
Gino A Cortopassi
金额：
$ 36.88万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213634
关键词：
4-ethoxymethylene-2-phenyl-2-oxazoline-5-one Acetyl-CoA C-Acetyltransferase Address Affect Age Aging Attenuated Binding Biological Assay Cells Cessation of life Cirrhosis Collagen Data Development Diet Disease Dominant-Negative Mutation Elderly Enzyme Activation Enzymes Fibrosis Fluorescence Resonance Energy Transfer Hepatic Fibrogenesis Hepatocyte Human Development Incidence Inflammation Inflammatory Insulin Resistance Interferometry Liver Liver diseases Longevity Lucigenin Mediating Medical Membrane Membrane Microdomains Microscopy Mitochondria Modeling Molecular Morbidity - disease rate Multienzyme Complexes Mus NADP NADPH Oxidase Obesity Epidemic Oxidation-Reduction Palmitates Pathogenesis Pathway interactions Play Prevalence Preventive treatment Process Production Protein Isoforms Proteins Reactive Oxygen Species Risk Role Severities Signal Transduction Site-Directed Mutagenesis Steatohepatitis Testing Tetanus Helper Peptide Therapeutic Time Toxic effect Treatment Protocols age related aged base design effective therapy endoplasmic reticulum stress experimental study fatty acid oxidation hepatocyte injury idebenone improved in vivo inhibitor/antagonist insulin sensitivity insulin signaling live cell imaging liver injury liver transplantation molecular domain mortality mouse model mutant nonalcoholic steatohepatitis novel older patient oxidation oxidative damage trafficking treatment strategy

项目摘要

Aging increases the prevalence and severity of liver disease, and this more severe, fibrotic form of liver disease is significantly increasing mortality in the elderly. Non-alcoholic steatohepatitis (NASH) is rapidly becoming the most common liver disease and presents with advanced fibrosis or cirrhosis in older patients. There is no approved medical therapy for NASH. The mechanistic factors that underlie the rising risk for fibrosis and death are not understood, although redox, inflammatory and mitochondrial factors have been implicated. We demonstrate for the first time that NASH in more common and severe in aged mice, and that Src homology 2 domain containing (Shc) protein and its newly identified ROS-producing partner NADPH oxidase 2 are induced. We propose a novel paradigm that aging accelerates NASH leading to cirrhosis; and the Shc proteins play in this process an essential role. Thus to study how longevity and redox pathways are integrated we hypothesized that during aging the combined effects of increased pShc46 and 52 activities are central to elicit an enhanced pro-oxidant, inflammatory and fibrogenic activity in NASH. To address this hypothesis we will focus on: 1) The molecular mechanism of Shc-p47phox binding, trafficking to the membrane, and the formation of the active NOX2 enzyme in hepatocytes; 2) The role of p46Shc in modulating palmitate oxidation, toxicity, and insulin resistance in hepatocytes; and 3) Determining the in vivo effects of Shc signaling on inflammation, insulin resistance, steatosis, oxidative injury and fibrosis in conditional hepatocyte-specific ShcKO mice (young vs. old) and DN models on NASH diets. We will also study the effects of Shc inhibition by idebenone on NASH in young and old mice both in preventive and treatment protocols. These studies will help in understanding age- specific profibrogenic pathways and set the frame for developing effective treatment options for NASH in the elderly.

衰老会增加肝病的患病率和严重程度，这种更严重，纤维化形式肝病的死亡率显着增加。非酒精性脂肪性肝炎（NASH）迅速成为最常见的肝病，并呈现晚期纤维化或老年患者的肝硬化。纳什没有批准的医疗疗法。机械尽管氧化还原，但尚不清楚纤维化和死亡风险上升风险的因素。炎症和线粒体因素已涉及。我们首次演示在老年小鼠中更常见和严重的nash，而SRC同源性2域含有（SHC）蛋白及其新鉴定的ROS产生伴侣NADPH氧化酶2是诱导。我们提出了一种新型的范式，使老化加速纳什导致肝硬化。和 SHC蛋白在此过程中起着重要作用。因此研究寿命和氧化还原整合了途径，我们假设在老化期间 PSHC46和52个活动增加至关重 NASH中的炎症和纤维化活性。为了解决这一假设，我们将重点关注： 1）SHC-P47Phox结合，运输与膜的分子机制，并肝细胞中活性NOX2酶的形成； 2）P46SHC在调节中的作用棕榈酸酯氧化，毒性和胰岛素耐药性； 3）确定IN SHC信号传导对炎症，胰岛素抵抗，脂肪变性，氧化损伤和有条件的肝细胞特异性SHCKO小鼠（Young vs. Old）和DN模型的纤维化饮食。我们还将研究IDEBENONO抑制SHC对年轻人和老年人NASH的影响在预防方案和治疗方案中均采用小鼠。这些研究将有助于了解年龄特定的成能途径，并为开发有效治疗选择的框架纳什在老年人中。