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

慢性肝病是美国第12大致死原因，每年导致≈死亡200万人 在世界范围内，使其成为一个主要的健康问题。肝纤维化是临床并发症的主要原因。 由于肥胖和NASH的全球流行，CLD的发病率进一步上升。尽管标识了密钥 促进肝纤维化的途径，如TGFb和PDGF，目前仍没有一种被批准的抗纤维化药物 治疗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。 进展期，发生肝硬变的风险增加6倍 谷丙转氨酶水平升高。同样，小鼠肝细胞死亡的遗传诱导足以引发 进展为纤维化。然而，细胞死亡促进纤维化的机制仍然知之甚少。 而且在治疗上没有被开发过。在这里，我们假设与损伤相关的分子模式(阻尼值)和 它们的受体可能在肝细胞死亡和肝纤维化之间提供了直接的联系。这样的一个 DAMP/DAMP受体系统将赋予肝星状细胞(HSC)，肝星状细胞是肝纤维化的主要细胞类型 肝脏，具有通过肝细胞释放的阻尼物感知肝损伤的能力，导致HSC激活和 纤维化是对肝细胞损伤的量身定做的反应。基于全基因组筛选，在这些筛选中我们 鉴定了几种富含HSC的候选DAMP受体，并在体外和体内进行了功能研究 分析，我们的建议将集中在P2RY14及其配体UDP-葡萄糖，UDP-半乳糖和UDP-葡萄糖醛酸 酸是肝脏中可能存在的促肝纤维化的DAMP/DAMP受体系统。在目标1中，我们将调查(I) 什么细胞死亡模式触发了这个DAMP/DAMP受体系统的激活；(Ii)通过什么机制 P2RY14及其配体影响HSC的激活、增殖和迁移；以及(Iii)通过以下方式确认与人类的相关性 检测患者P2YR14的表达和P2YR14配体及其介导的活化研究 人类的HSC。在目标2中，我们将确定P2RY14在肝纤维化中的作用，并特别关注 NASH，使用HSC特异性的P2RY14缺失策略以及P2RY14的药物抑制 建立P2RY14作为抗纤维化治疗的潜在靶点。总之，拟议的研究将确立 特定的湿-湿受体-配体对与细胞特异性表达模式相联系的新范式 肝细胞死亡与HSC活化和肝纤维化的关系，并可能为肝脏提供一个新的治疗靶点 纤维化症。 好了！

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. !