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 肥胖症患有多种伴随的代谢合并症，包括非酒精脂肪肝病（NAFLD）。 NAFLD现在是慢性肝病的主要原因，患病率临近30％ 人群，但实际上可能被认为是非酒精性脂肪性肝炎（NASH）的“前疾病”状态。 纳什（Nash 肝细胞癌，是肝移植最快的原因。纳什没有批准 药物治疗 - 随着与肥胖相关的纳什的患病率继续上升，可用的生命 移植仍然限制，这种未满足的需求变得更加紧迫。 Notch是对细胞命运决策至关重要的高度组成的蛋白质家族，但对 成熟组织中的缺口作用。我们的最初表征表明，缺口活性在低处存在 正常肝脏的水平，肥胖患者的肝脏以及饮食诱导或遗传小鼠的肝脏显着增加 肥胖模型，但在NASH患者中最高，并且与血浆显示显着的正相关 ALT和NAFLD活动得分。这项观察性研究促使了Pivens试验的试验子学，其中 我们观察到改善的NASH与较低的肝脏缺口活性有关。接下来，我们发现缺口 功能丧失的小鼠免受饮食诱导的脂肪性肝炎和纤维化的保护，而组成型活性 肝细胞缺口活性即使在食小鼠中也促使注射和纤维化。有趣的是，纳什 患者和小鼠的脂肪性肝炎模型，仅表达5种缺口配体中的1（JAG1）与 疾病病理学。这些结果表明，肝脏中以JAG1驱动的凹槽活性可能超过 生物标志物，但实际上是NASH/纤维化的机械决定因素，我们将在此应用中对其进行测试。在 AIM 1，我们研究肥胖中JAG1增加的机械决定者，发炎的肝脏，确定是否是否 肝细胞JAG1对于增加脂肪性肝炎中的肝脏凹口信号是必需的，并测试了新型JAG1是否 在AIM 2中，我们将测试是否更改 MCP1和骨桥的肝细胞分泌，均使用公正的屏幕确定 NASH小鼠的缺口活性肝细胞可以解释缺口介导的肝注射和纤维化 分别是这些分子介质的Notch诱导转录的基础机制。 实现此应用程序的目标将确定肝细胞缺口增加信号的机制 肥胖的肝脏，描述了缺口诱导的肝脏病理学的机械决定因素，并有可能导致 新型缺口抑制剂用于NASH和纤维化。