Jagged-Notch signaling in NASH/fibrosis

NASH/纤维化中的锯齿状Notch信号传导

基本信息

批准号：
10744371
负责人：
Utpal Pajvani
金额：
$ 57.73万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-15 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10744371
关键词：
Ablation Affect Animals Binding Binding Proteins Biology Biopsy Cell Separation Cells Cholesterol Cirrhosis Coculture Techniques Communication Complement Complement Activation Complication Critical Pathways Data Decision Making Development Diet Disease Doxycycline Endocrine Exposure to Fibrosis Fructose Gene Expression Genetic Genetic Transcription Goals Grant Hepatic Stellate Cell Hepatocyte Human Immune In Vitro Inflammation Injury Intervention LTBP2 gene Ligands Liver Liver Fibrosis LoxP-flanked allele Mediating Mediator Modeling Molecular Morbidity - disease rate Mus Obese Mice Obesity Obesity Epidemic Palmitates Pathogenesis Pathology Pathway interactions Patients Pharmacotherapy Phenotype Population Prevalence Profibrotic signal Recombinants Reporter Repression Reproducibility Risk Factors Role Series Severity of illness Signal Pathway Signal Transduction Sorting Steatohepatitis Testing Therapeutic Transforming Growth Factor beta Translating Wild Type Mouse Work attenuation chronic liver disease gain of function inhibitor liquid chromatography mass spectrometry liver biopsy liver development liver inflammation liver injury liver transplantation loss of function mortality mouse model non-alcoholic fatty liver disease nonalcoholic steatohepatitis notch protein novel obese patients obesogenic pharmacologic post intervention randomized, clinical trials response tool transcriptome sequencing validation studies

Ablation Affect Animals Binding Binding Proteins Biology Biopsy Cell Separation Cells Cholesterol Cirrhosis Coculture Techniques Communication Complement Complement Activation Complication Critical Pathways Data Decision Making Development Diet Disease Doxycycline Endocrine Exposure to Fibrosis Fructose Gene Expression Genetic Genetic Transcription Goals Grant Hepatic Stellate Cell Hepatocyte Human Immune In Vitro Inflammation Injury Intervention LTBP2 gene Ligands Liver Liver Fibrosis LoxP-flanked allele Mediating Mediator Modeling Molecular Morbidity - disease rate Mus Obese Mice Obesity Obesity Epidemic Palmitates Pathogenesis Pathology Pathway interactions Patients Pharmacotherapy Phenotype Population Prevalence Profibrotic signal Recombinants Reporter Repression Reproducibility Risk Factors Role Series Severity of illness Signal Pathway Signal Transduction Sorting Steatohepatitis Testing Therapeutic Transforming Growth Factor beta Translating Wild Type Mouse Work attenuation chronic liver disease gain of function inhibitor liquid chromatography mass spectrometry liver biopsy liver development liver inflammation liver injury liver transplantation loss of function mortality mouse model non-alcoholic fatty liver disease nonalcoholic steatohepatitis notch protein novel obese patients obesogenic pharmacologic post intervention randomized, clinical trials response tool transcriptome sequencing validation studies

展开

项目摘要

Project Abstract Obesity is the predominant risk factor for Non-Alcoholic Fatty Liver Disease (NAFLD), the leading cause for chronic liver disease with prevalence approaching 30% in certain populations. NAFLD, however, may in fact be considered a “pre-disease” state for Non-Alcoholic Steatohepatitis (NASH), which is defined by liver injury and associated inflammation and fibrosis. NASH has no approved pharmacotherapy, and is thus the fastest-growing reason for liver transplantation. As the prevalence of obesity-related NASH continues to rise, and available livers for transplantation remain limiting, this unmet need grows more urgent. In obese mice and patients undergoing liver biopsy for suspected NASH, we observed an unexpected and aberrant activation of hepatocyte Notch, a morphogenic pathway critical for cell fate decision-making in normal liver development. Validation studies revealed that Notch activity was positively associated with markers of liver inflammation and fibrosis and tracked with disease severity in patients with pre- and post-intervention biopsies in randomized clinical trials. Our mechanistic work in the first cycle of this grant showed that Notch is causal to disease, as hepatocyte-specific Notch loss-of-function – by genetic or pharmacologic ablation of either the Notch ligand Jagged1, or by blocking Notch transcriptional activity – protected mice from diet- induced steatohepatitis and fibrosis, whereas forced Jagged1 or Notch activity exacerbated inflammation and fibrosis phenotypes. To determine downstream factors responsible for Notch activity, we performed a series of RNAseq and scRNAseq screens that revealed LTBP3 as a novel Notch target. In Aim 1, we study with novel genetic and pharmacologic tools whether increased hepatocyte LTBP3 secretion mediates Notch-induced hepatic inflammation and fibrosis, and potential mechanisms of these effects. Beyond endocrine communication, hepatocytes can directly interact with non-parenchymal cells, including hepatic stellate cells (HSC), to determine obesity-induced liver pathology. Intriguingly, we observed increased Notch activity in HSC isolated from NASH diet-fed mice; other preliminary data suggest that the same proximal signal (Jagged1) may mediate HSC activation and lead to liver fibrosis, which we test in Aim 2. Finally, we leverage a novel mouse model of reversible hepatocyte Notch activity to discover potential fibrosis regression pathways in Aim 3. Achieving the goals of this application will identify mechanistic determinants of Notch-induced liver pathology and potentially lead to application of novel Jagged-Notch or LTBP3 inhibitors for NASH and fibrosis.

项目摘要肥胖是非酒精性脂肪肝疾病（NAFLD）的主要危险因素，这是主要原因在某些人群中，患病率的慢性肝病接近30％。但是，NAFLD实际上可能是被认为是非酒精性脂肪性肝炎（NASH）的“疾病前”状态，该状态是由肝损伤和相关的炎症和纤维化。纳什没有批准的药物疗法，因此增长最快肝移植的原因。随着与肥胖相关的纳什的患病率继续上升，可用的生活为了移植保持限制，这种未满足的需求变得更加紧迫。在肥胖的小鼠和接受肝活检的疑似纳什的患者中，我们观察到了出乎意料的，肝细胞缺口的异常激活，这是一种对正常细胞命运决策至关重要的形态学途径肝脏发育。验证研究表明，Notch活性与标记呈正相关肝脏炎症和纤维化，并在干预前后患者的疾病严重程度跟踪随机临床试验中的活检。我们在这笔赠款的第一个周期中的机械工作表明Notch是疾病的因果，作为肝细胞特异性障碍的功能丧失 - 遗传或药理消融 Notch配体Jagged1或通过阻断缺口转录活性 - 保护小鼠免受饮食的保护诱导脂肪性肝炎和纤维化，而强迫锯齿状1或缺口活性加剧了注射和纤维化表型。为了确定负责Notch活动的下游因素，我们进行了一系列 RNASEQ和SCRNASEQ屏幕揭示了LTBP3是一种新的缺口靶标。在AIM 1中，我们学习新颖遗传和药物工具是否增加了肝细胞LTBP3分泌是否介导了Notch诱导的肝炎炎症和纤维化，以及这些作用的潜在机制。超越内分泌通信，肝细胞可以直接与非核细胞相互作用，包括肝星细胞（HSC），确定肥胖引起的肝脏病理学。有趣的是，我们观察到HSC中的缺口活性增加从纳什饮食喂养的小鼠中分离出来；其他初步数据表明，相同的代理信号（JAGGED1）可能介导HSC激活并导致肝纤维化，我们在AIM 2中进行测试。最后，我们利用了一种新的小鼠可逆肝细胞缺口活性的模型，以发现AIM 3中潜在的纤维化回归途径。实现此应用程序的目标将确定Notch诱导的肝脏病理学的机械决定者并有可能导致新颖的锯齿状 - 网状或LTBP3抑制剂用于NASH和纤维化。