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: 10436913
• 负责人: Gino A Cortopassi
• 金额: $ 37.55万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436913
• 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; 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.

老龄化增加了肝病的患病率和严重程度，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。非酒精性脂肪肝炎 NASH正在迅速成为最常见的肝脏疾病，并表现为晚期纤维化 或肝硬化。目前尚无针对NASH的获批药物治疗。机械论 纤维化和死亡风险上升的潜在因素尚不清楚，尽管氧化还原， 炎症和线粒体因子也有牵连。我们首次展示了 NASH在老年小鼠中更常见和严重，Src同源2结构域 含有（Shc）蛋白及其新鉴定的产生ROS的伴侣NADPH氧化酶2， 诱导。我们提出了一种新的范式，即衰老加速NASH导致肝硬化; Shc蛋白在此过程中起重要作用。从而研究长寿和氧化还原 我们假设，在衰老过程中， 增加的pShc 46和52活性是引发增强的促氧化剂的关键， 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-p47 phox结合、转运至细胞膜及细胞凋亡的分子机制 肝细胞中活性NOX 2酶的形成; 2）p46 Shc在调节 肝细胞中的棕榈酸氧化、毒性和胰岛素抵抗;以及3）确定肝细胞中的胰岛素抵抗。 Shc信号传导对炎症、胰岛素抵抗、脂肪变性、氧化损伤和 NASH条件性肝细胞特异性ShcKO小鼠（年轻与老年）和DN模型中的纤维化 节食。我们还将研究艾地苯醌抑制Shc对青年和老年NASH的影响 预防和治疗方案中的小鼠。这些研究将有助于了解年龄- 特定的促纤维化途径，并为开发有效的治疗方案提供框架， 老年人NASH

项目成果

Shc inhibitor idebenone ameliorates liver injury and fibrosis in dietary NASH in mice.

• DOI: 10.1002/jbt.22876
• 发表时间: 2021-10
• 期刊: JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
• 影响因子: 3.6
• 作者: Jiang, Joy X.;Tomilov, Alexey;Montgomery, Claire;Hui, Chun Kui;Torok, Natalie J.;Cortopassi, Gino
• 通讯作者: Cortopassi, Gino