Dectin-1 Regulates Chronic Liver Fibro-inflammatory Disease

 描述（由申请人提供）：很少有有效的临床策略来预防或治疗肝纤维化或随后的肝硬化。跨膜受体Dectin-1是模式识别受体的C型凝集素家族的成员，其是Toll样受体（TLR）家族的表亲。尽管Dectin-1是对真菌病原体的先天免疫应答所必需的，但它在任何情况下都不具有调节无菌炎症的既定作用。基于可靠的初步数据，我们的假设是Dectin-1信号传导通过两种不同的机制来保护肝纤维化：（i）限定响应于肝损伤的TLR 4活化，和（ii）直接促进肝再生。这一提议非常新颖，因为这是第一次研究Dectin-1在非病原体驱动的无菌炎症中的作用。在目的1中，我们将研究新型Dectin-1配体的表达和激活的Dectin-1信号传导中间体在小鼠和人肝纤维化中的上调。这些数据将表明内源性Dectin-1信号传导与人类和小鼠肝纤维化调节的相关性。然后，我们将通过直接评估Dectin-1的缺失是否加剧肝纤维化以及Dectin-1的连接是否保护肝纤维化来测试我们的主要假设。在目标2中，我们将确定Dectin-1信号传导是否通过减轻TLR 4活化来保护肝纤维化。我们将研究肝脏巨噬细胞和肝星状细胞中Dectin-1和TLR 4之间的新型交叉调节，并确定肝脏疾病中Dectin-1抑制TLR 4信号传导的复杂机制。总的来说，这些实验将为Dectin-1如何抑制TLR 4介导的肝纤维炎性疾病提供机制性见解。在目标3中，我们将探索一种独立于Dectin-1-TLR 4界面的机制途径。具体而言，我们假设Dectin-1通过促进肝再生来减轻肝纤维化。我们将研究在肝纤维化和部分肝切除术后，Dectin-1在肝细胞增殖中的作用，并确定该过程的介质。当完成时，我们希望我们的工作将表明Dectin-1信号传导可以防止肝纤维炎性疾病，并可能成为疾病预防或实验治疗的有吸引力的靶点。此外，我们工作的重要性超出了慢性肝纤维化;它有望破译控制肝再生和无菌炎症调节的关键信号机制，这些机制是维持健康和疾病中生理稳态所必需的。

 DESCRIPTION (provided by applicant): There are few effective clinical strategies to prevent or treat liver fibrosis or ensuing cirrhosis. The transmembrane receptor Dectin-1 is a member of the C-type lectin family of pattern recognition receptors which are cousins of the Toll-like receptor (TLR) family. Although Dectin-1 is required for the innate immune response to fungal pathogens, it does not have an established role in modulating sterile inflammation in any context. Based on robust preliminary data, our hypothesis is that Dectin-1 signaling protects against liver fibrosis by two distinct mechanisms: (i) delimiting TLR4 activation in response to hepatic injury, and (ii) directly promoting hepatic regeneration. This proposal is highly novel, given that this is the first investigation of a role for Dectin-1 in non-pathogen-driven sterile inflammation. In Aim 1 we will investigate the expression of novel Dectin-1 ligands and upregulation of activated Dectin-1 signaling intermediates in murine and human liver fibrosis. These data will indicate the relevance of endogenous Dectin-1 signaling to the modulation of liver fibrosis in humans and mice. We will then test our primary hypothesis by directly assessing whether deletion of Dectin-1 exacerbates liver fibrosis and whether ligation of Dectin-1 protects against liver fibrosis. In Aim 2 we will determine whether Dectin-1 signaling protects against live fibrosis by mitigating TLR4 activation. We will investigate novel cross-regulation between Dectin-1 and TLR4 in liver macrophages and hepatic stellate cells and determine the complex mechanisms governing Dectin-1 suppression of TLR4 signaling in vivo in liver disease. Collectively, these experiments will provide mechanistic insight into how Dectin-1 suppresses TLR4-mediated hepatic fibro-inflammatory disease. In Aim 3 we will explore a mechanistic avenue that is independent of the Dectin-1-TLR4 interface. Specifically, we postulate that Dectin-1 mitigates liver fibrosis by promoting hepatic regeneration. We will investigate the role o Dectin-1 in hepatocyte proliferation in the fibrotic liver and after partial hepatectomy and determine the mediators of this process. When completed, we expect that our work will suggest that Dectin-1 signaling protects against hepatic fibro-inflammatory disease and may be an attractive target for disease prophylaxis or experimental therapies. Moreover, the importance of our work extends beyond chronic liver fibrosis; it promises to decipher critical signaling mechanisms that govern hepatic regeneration and regulation of sterile inflammation which are necessary to maintain physiologic homeostasis in health and disease.