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

• 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
• 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

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，而这种更严重的纤维化形式 肝病的发病率显著增加了老年人的死亡率。非酒精性脂肪性肝炎 (NASH)正迅速成为最常见的肝病，并表现为晚期纤维化 或老年患者的肝硬变。目前还没有批准的治疗NASH的药物。机械论 导致纤维化和死亡风险上升的因素尚不清楚，尽管氧化还原， 炎症和线粒体因素也有牵连。我们第一次演示了 NASH在老年小鼠中更常见和更严重，而且Src同源2结构域 含有(Shc)蛋白及其新发现的ROS产生伙伴NADPH氧化酶2是 诱导性。我们提出了一个新的范式，即衰老加速NASH导致肝硬变； Shc蛋白在这一过程中起着至关重要的作用。从而研究长寿与氧化还原 我们假设，在衰老过程中， PShc46和52活性的增加是诱导增强的促氧化剂的核心， NASH的炎症和纤维化活性。为了解决这一假设，我们将重点放在： 1)Shc-p47Phox结合、转运到细胞膜的分子机制 肝细胞中活性NOX2酶的形成；2)p46Shc在调节中的作用 肝细胞中棕榈酸酯的氧化、毒性和胰岛素抵抗；以及3)测定 Shc信号在炎症、胰岛素抵抗、脂肪变性、氧化损伤和 条件性肝细胞特异性ShcKO小鼠(青年与老年)和NASH糖尿病肾病模型中的纤维化 节食。我们还将研究艾地苯酮抑制Shc对青年和老年NASH的影响 无论是预防还是治疗方案中的小鼠。这些研究将有助于理解年龄- 并为开发有效的治疗方案奠定了框架。 纳什在老年。