Jagged-Notch signaling in NASH/fibrosis

NASH/纤维化中的锯齿状Notch信号传导

• 批准号: 10338130
• 负责人: Utpal Pajvani
• 金额: $ 41.8万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10338130
• 关键词: Address; Attenuated; Biological Markers; Biopsy; CCL2 gene; Cells; Cessation of life; Cirrhosis; Cross-Sectional Studies; Data; Decision Making; Development; Diet; Disease; Disease Progression; ES01; Endosomes; Eye; Fatty acid glycerol esters; Fibrinogen; Fibrosis; Genetic; Genetic Transcription; Goals; Hepatic; Hepatic Stellate Cell; Hepatocyte; Heterogeneity; Human; Immune; Inflammation; Inflammatory; Insulin Resistance; JAG1 protein; Knock-out; Lead; Ligands; Liver; Liver Fibrosis; Mediating; Mediator of activation protein; Membrane; Metabolic; Molecular; Morbidity - disease rate; Mus; Obesity; Obesity Epidemic; Observational Study; Pathology; Pathway interactions; Patients; Pharmacology; Pharmacotherapy; Phenotype; Pioglitazone; Placebos; Plasma; Play; Population; Prevalence; Primary carcinoma of the liver cells; Process; Protein Family; Recycling; Regulation; Reporter; Role; Signal Transduction; Steatohepatitis; Stimulus; Testing; Therapeutic; Tissues; Toxic effect; Translations; Uncertainty; Variant; Vimentin; Vitamin E; biliary tract; chronic liver disease; comorbidity; improved; inhibitor; liver biopsy; liver inflammation; liver injury; liver transplantation; loss of function; mortality; mouse model; nicastrin protein; non-alcoholic fatty liver disease; non-diabetic; nonalcoholic steatohepatitis; notch protein; novel; novel marker; obese patients; osteopontin; receptor; recruit; response; transcriptome sequencing

Project Abstract Obesity has multiple attendant metabolic comorbidities, including Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD is now the leading cause of chronic liver disease, with prevalence approaching 30% in certain populations, but may in fact be considered a “pre-disease” state for Non-Alcoholic Steatohepatitis (NASH). NASH, defined by hepatocyte damage with associated inflammation and fibrosis, predisposes to cirrhosis and hepatocellular cancer, and is the fastest-growing reason for liver transplantation. NASH has no approved pharmacotherapy – as the prevalence of obesity-related NASH continues to rise, and available livers for transplantation remain limiting, this unmet need grows more urgent. Notch is a highly conserved family of proteins critical for cell fate decision-making, but less is known about Notch action in mature tissue. Our initial characterization demonstrated that Notch activity is present at low levels in normal liver, increases markedly in livers from obese patients and diet-induced or genetic mouse models of obesity, but is highest in patients with NASH and shows significant positive correlations with plasma ALT and NAFLD Activity Score. This observational study prompted a pilot sub-study of the PIVENS trial, where we observed that improved NASH is associated with lower hepatic Notch activity. We next found that Notch loss-of-function mice are protected from diet-induced steatohepatitis and fibrosis, whereas constitutively-active hepatocyte Notch activity prompted inflammation and fibrosis even in chow-fed mice. Intriguingly, in NASH patients and mouse models of steatohepatitis, expression of only 1 of 5 Notch ligands (Jag1) correlates with disease pathology. These results suggest that Jag1-driven Notch activity in liver may be more than a biomarker, but actually a mechanistic determinant of NASH/fibrosis, which we will test in this application. In Aim 1, we study mechanistic determinants of increased Jag1 in the obese, inflamed liver, determine whether hepatocyte Jag1 is necessary for increased liver Notch signaling in steatohepatitis and test whether novel Jag1 inhibitors may reduce obesity-induced liver inflammation and fibrosis. In Aim 2, we will test whether changes in hepatocyte secretion of MCP1 and Osteopontin, both identified using an unbiased screen for markers of Notch-active hepatocytes in mice with NASH, can explain Notch-mediated hepatic inflammation and fibrosis respectively, as well as mechanism underlying Notch-induced transcription of these molecular mediators. Achieving the goals of this application will identify the mechanism of increased hepatocyte Notch signaling in the obese liver, delineate the mechanistic determinants of Notch-induced liver pathology and potentially lead to application of novel Notch inhibitors for NASH and fibrosis.

项目摘要 肥胖会引起多种代谢合并症，包括非酒精性脂肪肝（NAFLD）。 NAFLD 现在是慢性肝病的主要原因，某些地区的患病率接近 30% 人群，但实际上可能被视为非酒精性脂肪性肝炎 (NASH) 的“病前”状态。 NASH 的定义是伴有炎症和纤维化的肝细胞损伤，容易导致肝硬化和 肝细胞癌，并且是NASH尚未获得批准的增长最快的原因。 药物治疗——随着肥胖相关 NASH 的患病率持续上升，可用的肝脏 移植仍然受到限制，这种未满足的需求变得更加紧迫。 Notch 是一个高度保守的蛋白质家族，对细胞命运决策至关重要，但人们对其知之甚少 我们的初步表征表明，Notch 活性较低。 正常肝脏中的水平，肥胖患者和饮食诱导或遗传小鼠的肝脏中显着增加 肥胖模型，但在 NASH 患者中最高，并且与血浆呈显着正相关 ALT 和 NAFLD 活动评分 这项观察性研究促进了 PIVENS 试验的试点子研究，其中 我们观察到 NASH 的改善与肝脏 Notch 活性的降低有关。 功能丧失的小鼠可以免受饮食诱导的脂肪性肝炎和纤维化的影响，而组成性活跃的小鼠 有趣的是，即使在 NASH 喂养的小鼠中，肝细胞 Notch 活性也会引起炎症和纤维化。 在脂肪性肝炎患者和小鼠模型中，5 个 Notch 配体 (Jag1) 中仅 1 个的表达与 这些结果表明肝脏中 Jag1 驱动的 Notch 活性可能不仅仅是一个。 生物标志物，但实际上是 NASH/纤维化的机制决定因素，我们将在本应用中对其进行测试。 目标 1，我们研究肥胖、发炎肝脏中 Jag1 增加的机制决定因素，确定是否 肝细胞 Jag1 对于脂肪性肝炎中肝脏 Notch 信号传导的增加是必需的，并测试新型 Jag1 是否存在 抑制剂可能会减少肥胖引起的肝脏炎症和纤维化 在目标 2 中，我们将测试是否会发生变化。 MCP1 和骨桥蛋白的肝细胞分泌，均通过无偏筛选标记物进行鉴定 NASH 小鼠的 Notch 活性肝细胞可以解释 Notch 介导的肝脏炎症和纤维化 分别，以及Notch诱导这些分子介质转录的机制。 实现本申请的目标将确定肝细胞 Notch 信号传导增加的机制 肥胖肝脏，描绘了 Notch 诱导的肝脏病理学的机制决定因素，并可能导致 新型Notch抑制剂在NASH和纤维化中的应用。