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) 是美国第 12 大死亡原因，每年导致约 200 万人死亡 在世界范围内，使其成为一个主要的健康问题。肝纤维化是大多数临床并发症的原因 由于肥胖和 NASH 的全球流行，慢性肺病 (CLD) 的发病率进一步上升。尽管识别了密钥 尽管 TGFb 和 PDGF 等促进肝纤维化的途径，但目前还没有一种经批准的抗纤维化药物 肝纤维化患者的药物。从机制层面来看，肝细胞死亡是肝病的关键驱动因素 进展，超过两倍以上的患者发生肝硬化的风险增加 6 倍 谷丙转氨酶（ALT）水平升高。同样，小鼠肝细胞死亡的基因诱导足以引发 进展为纤维化。然而，细胞死亡促进纤维化的机制仍知之甚少 并且在治疗上尚未开发。在这里，我们假设损伤相关分子模式（DAMP）和 它们的受体可能提供肝细胞死亡和肝脏纤维形成之间的直接联系。这样一个 DAMP/DAMP 受体系统将赋予肝星状细胞 (HSC)，这是肝脏中主要的纤维化细胞类型 肝脏，具有通过肝细胞释放的 DAMP 感知肝损伤的能力，从而导致 HSC 激活和 纤维发生作为对肝细胞损伤的定制反应。基于全基因组筛选，我们 鉴定了几种富含 HSC 的候选 DAMP 受体，并随后在体外和体内发挥功能 分析中，我们的建议将重点关注 P2RY14 及其配体 UDP-葡萄糖、UDP-半乳糖和 UDP-葡萄糖醛酸 酸作为肝脏中候选的促纤维化 DAMP/DAMP 受体系统。在目标 1 中，我们将调查 (i) 哪种细胞死亡模式会触发 DAMP/DAMP 受体系统的激活； (二) 机制 P2RY14及其配体影响HSC活化、增殖和迁移； (iii) 确认人类相关性 确定患者中 P2YR14 表达和 P2YR14 配体并研究 P2RY14 介导的激活 人类 HSC。在目标 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 的药理学抑制 确立 P2RY14 作为抗纤维化治疗的潜在靶点。拟议的研究将共同​​建立 特定 DAMP-DAMP 受体-配体对与细胞特异性表达模式链接的新范例 肝细胞死亡导致HSC活化和肝纤维化，可能为肝脏疾病提供新的治疗靶点 纤维化。 ！