DAMPs and Their Receptors Link Hepatocyte Death to HSC Activation and Liver Fibrosis

DAMP 及其受体将肝细胞死亡与 HSC 激活和肝纤维化联系起来

• 批准号: 9917105
• 负责人: Robert F. Schwabe
• 金额: $ 52万
• 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: 2019-09-20 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917105
• 关键词: Affect; Apoptosis; Area; Biliary; Biological Assay; Cell Death; Cell Proliferation; Cells; Cessation of life; Characteristics; Cirrhosis; Clinical; Coculture Techniques; Data; Development; Disease; Disease Progression; Disease model; FDA approved; Fibroblasts; Fibrosis; Genes; Genetic Induction; Glucose; Health; Hepatic Fibrogenesis; Hepatic Stellate Cell; Hepatocyte; Human; In Vitro; Injury; Knock-out; Knockout Mice; Ligands; Link; Liver; Liver Fibrosis; Liver diseases; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Necrosis; Obesity; Obesity Epidemic; Outcome; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Platelet-Derived Growth Factor; Population; Risk; Role; Serum; Signal Transduction; Site; System; Testing; Therapeutic; Up-Regulation; Uridine Diphosphate Galactose; Uridine Diphosphate Glucuronic Acid; base; cell motility; cell type; chronic liver disease; experimental study; fibrogenesis; genome wide screen; high risk; in vivo; in vivo evaluation; liver development; liver injury; migration; mortality; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; receptor; response; single-cell RNA sequencing; whole genome

Chronic liver disease (CLD) is the 12th leading cause of mortality in the US and causes ≈2 million deaths/year world-wide, making it a major health problem. Liver fibrosis contributes to the majority of clinical complications of CLD and is further on the rise due to the global epidemic of obesity and NASH. Despite identification of key pathways that promote liver fibrosis such as TGFb and PDGF, there is still not a single approved anti-fibrogenic drug for patients with liver fibrosis. On a mechanistic level, hepatocellular death is a key driver of liver disease progression, with a 6-fold higher risk for the development of cirrhosis in patients with great than two-fold increased ALT levels. Likewise, genetic induction of hepatocellular death in mice is sufficient to trigger the progression to fibrosis. However, mechanisms by which cell death promotes fibrosis remain poorly understood and therapeutically unexploited. Here, we hypothesize that damage-associated molecular patterns (DAMPs) and their receptors may provide a direct link between hepatocyte death and fibrogenesis in the liver. Such a DAMP/DAMP receptor system would endow hepatic stellate cells (HSC), the primary fibrogenic cell type in the liver, with the ability to sense liver injury via hepatocyte-released DAMPs, resulting in HSC activation and fibrogenesis as tailored response to hepatocellular injury. Based on whole genome screens, in which we identified several HSC-enriched candidate DAMP receptors, and subsequent functional in vitro and in vivo assays, our proposal will focus on P2RY14 and its ligands UDP-glucose, UDP-galactose and UDP-glucuronic acid as the candidate profibrogenic DAMP/DAMP receptor system in the liver. In Aim 1, we will investigate (i) which modes of cell death trigger activation of this DAMP/DAMP receptor system; (ii) the mechanisms by which P2RY14 and its ligands affect HSC activation, proliferation and migration; and (iii) confirm human relevance by determining P2YR14 expression and P2YR14 ligands in patients and by studying P2RY14-mediated activation of human HSC. In Aim 2, we will determine the contribution of P2RY14 to liver fibrosis with a particular focus on NASH, using HSC-specific P2RY14 deletion strategies as well as pharmacologic inhibition of P2RY14 to establish P2RY14 as potential target for antifibrogenic therapies. Together, the proposed studies will establish the new paradigm that a specific DAMP-DAMP receptor-ligand pair with cell-specific expression patterns links hepatocyte death to HSC activation and liver fibrosis, and that it may provide a novel therapeutic target for liver fibrosis. !

慢性肝病（CLD）是美国死亡率的第12个主要原因，每年造成约200万人死亡 在全球范围内，使其成为一个主要的健康问题。肝纤维化有助于大多数临床并发症 由于肥胖和NASH的全球流行，CLD的进一步增加了。尽管确定了钥匙 促进肝纤维化（例如TGFB和PDGF）的途径，仍然没有一个批准的抗纤维化 肝纤维化患者的药物。在机械水平上，肝细胞死亡是肝病的关键驱动力 进展，肝硬化的风险高6倍以上的患者 ALT水平提高。同样，小鼠肝细胞死亡的遗传诱导足以触发 发展为纤维化。但是，细胞死亡促进纤维化的机制仍然很少了解 和热未爆。在这里，我们假设与损伤相关的分子模式（潮湿）和 他们的接收器可能会在肝细胞死亡与肝脏中的纤维发生之间提供直接联系。 潮湿/潮湿受体系统将赋予肝脏星状细胞（HSC），这是一级纤维化细胞类型 肝脏，能够通过肝细胞释放的潮湿感受肝损伤，从而导致HSC激活和 纤维发生是对肝细胞损伤的量身定制反应。基于整个基因组屏幕，我们 鉴定了几种富含HSC的候选潮湿受体，随后在体外和体内发挥了功能 测定法，我们的建议将重点放在P2RY14及其配体UDP-葡萄糖，UDP-Galactose和UDP-glucuroons上 酸作为肝脏中的候选纤维化潮湿/潮湿受体系统。在AIM 1中，我们将调查（i） 细胞死亡的哪种模式触发了该潮湿/潮湿受体系统的激活； （ii） P2RY14及其配体会影响HSC激活，增殖和迁移。 （iii）通过 确定患者中的P2YR14表达和P2YR14配体，并研究P2RY14介导的激活 人类HSC。在AIM 2中，我们将确定P2RY14对肝纤维化的贡献，特别关注 NASH，使用HSC特异性P2RY14缺失策略以及P2RY14的药物抑制作用 建立P2RY14作为抗纤维化疗法的潜在靶标。拟议的研究将共同​​建立 具有细胞特异性表达模式链接的特定潮湿接收器配体的新范式是 HSC激活和肝纤维化的肝细胞死亡，并且可能为肝脏提供新的治疗靶点 纤维化。 呢