Dectin-1 Regulates Chronic Liver Fibro-inflammatory Disease

Dectin-1 调节慢性肝纤维炎症性疾病

• 批准号: 9322384
• 负责人: George Miller
• 金额: $ 42.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9322384
• 关键词: Adaptor Signaling Protein; Antifungal Agents; Apoptotic; C-Type Lectins; Categories; Cells; Chronic; Cirrhosis; Clinical; Complex; Data; Disease; Etiology; Extracellular Matrix; Family; Fibrosis; Health; Hepatic; Hepatic Stellate Cell; Hepatocyte; Homeostasis; Human; Immune; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Investigation; Investigational Therapies; Kupffer Cells; Leukocytes; Ligands; Ligation; Link; Liver; Liver Fibrosis; Liver diseases; Mediating; Mediator of activation protein; Metabolic Diseases; Molecular; Mus; Natural regeneration; Necrosis; Partial Hepatectomy; Pathogenicity; Pattern; Pattern recognition receptor; Process; Prophylactic treatment; Public Health; Recruitment Activity; Regulation; Role; Signal Transduction; Sterility; TLR4 gene; Testing; Tissues; Toll-like receptors; Toxin; Up-Regulation; Viral hepatitis; Work; base; beta-Glucans; dectin 1; experimental study; in vivo; insight; intrahepatic; liver cell proliferation; liver injury; macrophage; member; novel; pathogen; prevent; public health relevance; receptor; response

 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.

 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之而来的肝硬化。跨膜受体 Dectin-1 是模式识别受体 C 型凝集素家族的成员，该家族是 Toll 样受体 (TLR) 家族的近亲。尽管 Dectin-1 是针对真菌病原体的先天免疫反应所必需的，但它在任何情况下都没有在调节无菌炎症方面发挥确定的作用。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防止肝纤维化：(i) 限制 TLR4 激活以响应肝损伤，以及 (ii) 直接促进肝再生。鉴于这是对 Dectin-1 在非病原体驱动的无菌炎症中作用的首次研究，该提议非常新颖。在目标 1 中，我们将研究小鼠和人类肝纤维化中新型 Dectin-1 配体的表达以及激活的 Dectin-1 信号中间体的上调。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 的缺失是否会加剧肝纤维化以及 Dectin-1 的连接是否可以防止肝纤维化来检验我们的主要假设。在目标 2 中，我们将确定 Dectin-1 信号传导是否通过减轻 TLR4 激活来防止活纤维化。我们将研究肝脏巨噬细胞和肝星状细胞中 Dectin-1 和 TLR4 之间的新型交叉调节，并确定肝脏疾病体内 Dectin-1 抑制 TLR4 信号转导的复杂机制。总的来说，这些实验将为 Dectin-1 如何抑制 TLR4 介导的肝纤维炎症性疾病提供机制见解。在目标 3 中，我们将探索独立于 Dectin-1-TLR4 接口的机制途径。具体来说，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 Dectin-1 在纤维化肝脏中和部分肝切除术后肝细胞增殖中的作用，并确定该过程的介质。完成后，我们预计我们的工作将表明 Dectin-1 信号传导可预防肝纤维炎症性疾病，并可能成为疾病预防或实验治疗的有吸引力的目标。此外，我们工作的重要性不仅仅局限于慢性肝纤维化；它有望破译控制肝再生和无菌炎症调节的关键信号机制，这对于维持健康和疾病的生理稳态是必需的。