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 肥胖有多种伴随的代谢合并症，包括非酒精性脂肪肝（NAFLD）。 NAFLD现在是慢性肝病的主要原因，在某些国家的患病率接近30%。 在某些人群中，脂肪性肝炎是一种慢性疾病，但实际上可能被认为是非酒精性脂肪性肝炎（NASH）的“疾病前”状态。 NASH，定义为肝细胞损伤与相关炎症和纤维化，易发生肝硬化和肝硬化。 肝细胞癌，是肝移植增长最快的原因。NASH没有批准 药物治疗-随着肥胖相关NASH的患病率持续上升， 移植仍然有限，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，对细胞命运的决定至关重要，但对Notch基因的表达知之甚少。 成熟组织中的切口作用。我们的初步表征表明，Notch活性以低浓度存在。 在正常肝脏中的水平，在肥胖患者和饮食诱导或遗传小鼠的肝脏中显著增加 肥胖模型，但在NASH患者中最高，并显示与血浆 ALT和NAFLD活动评分。这项观察性研究促使PIVENS试验进行了一项先导子研究， 我们观察到改善的NASH与较低的肝Notch活性相关。我们接下来发现了Notch 功能丧失的小鼠被保护免于饮食诱导的脂肪性肝炎和纤维化，而组成性活性的小鼠被保护免于饮食诱导的脂肪性肝炎和纤维化。 肝细胞Notch活性甚至在普通饲料喂养小鼠中也引起炎症和纤维化。有趣的是，在NASH中 在脂肪性肝炎的患者和小鼠模型中，5种Notch配体中只有1种（Jag 1）的表达与 疾病病理学这些结果表明，肝脏中Jag 1驱动的Notch活性可能不仅仅是 这是一种生物标志物，但实际上是NASH/纤维化的机制决定因素，我们将在本申请中对其进行测试。在 目的1，我们研究肥胖、炎症肝脏中Jag 1增加的机制决定因素，确定是否 肝细胞Jag 1是脂肪性肝炎中增加肝脏Notch信号传导所必需的， 抑制剂可以减少肥胖诱导的肝脏炎症和纤维化。在目标2中，我们将测试 MCP 1和骨桥蛋白的肝细胞分泌，两者均使用无偏筛选标记物鉴定， NASH小鼠中Notch活性肝细胞可以解释Notch介导的肝脏炎症和纤维化 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， 肥胖的肝脏，描绘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。