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: 10224799
• 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/10224799
• 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; 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; hepatocellular injury; hepatocyte injury; 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1200万人死亡 全球范围内，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，CLD的发病率进一步上升。尽管识别了关键 虽然目前还没有一种单一的被批准的抗纤维化的药物， 用于肝纤维化患者的药物。在机制层面上，肝细胞死亡是肝脏疾病的关键驱动因素 进展，在大于2倍的患者中，发生肝硬化的风险高6倍。 ALT水平升高。同样地，小鼠肝细胞死亡的遗传诱导足以触发 进展为纤维化。然而，细胞死亡促进纤维化的机制仍然知之甚少 而且在治疗上未被利用在这里，我们假设损伤相关分子模式（DAMP）和 它们的受体可以提供肝细胞死亡和肝纤维化之间的直接联系。这样的 DAMP/DAMP受体系统将赋予肝星状细胞（HSC），肝纤维化中的主要纤维化细胞类型。 肝脏，能够通过肝细胞释放的DAMPs感知肝脏损伤，导致HSC激活， 肝纤维化是对肝细胞损伤的定制反应。基于全基因组筛选，其中我们 鉴定了几种富含HSC的候选DAMP受体，并随后在体外和体内进行了功能性研究。 我们的建议将集中在P2 RY 14及其配体UDP-葡萄糖，UDP-半乳糖和UDP-葡萄糖醛酸 在肝脏中，DAMP酸作为候选的促纤维化DAMP/DAMP受体系统。在目标1中，我们将研究（i） 哪种细胞死亡模式触发这种DAMP/DAMP受体系统的激活;（ii） P2 RY 14及其配体影响HSC活化、增殖和迁移;和（iii）通过以下方法证实人相关性： 通过研究P2 RY 14介导的活化，确定患者中P2 YR 14表达和P2 YR 14配体 人类HSC在目标2中，我们将确定P2 RY 14对肝纤维化的贡献，特别关注 NASH，使用HSC特异性P2 RY 14缺失策略以及P2 RY 14的药理学抑制， 确立P2 RY 14作为抗纤维化治疗潜在靶点。这些拟议的研究将共同建立 一个新的范例，一个特定的DAMP-DAMP受体-配体对与细胞特异性表达模式的联系 肝细胞死亡对HSC活化和肝纤维化的影响，它可能为肝脏疾病的治疗提供新的靶点。 纤维化 !