Fibrocytes regulate liver fibrosis

纤维细胞调节肝纤维化

• 批准号: 9218867
• 负责人: Tatiana Kisseleva
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9218867
• 关键词: 5' Untranslated Regions; Ablation; Alpha Cell; Amyloid; Anti-Inflammatory Agents; Anti-inflammatory; Archives; Attenuated; Biology; Bone Marrow; Cells; Chronic; Cirrhosis; Clinical Trials; Collagen; Collagen Type I; DDR1 gene; Data; Deposition; Development; Diet; Diphtheria Toxin; Enhancers; Etiology; Extracellular Matrix Proteins; Fibroblast Growth Factor; Fibrosis; Genetic; Goals; Healthcare; Hematopoietic; Hepatic; ITGAM gene; Inflammation; Inflammatory; Injury; Injury to Liver; Integrins; Interleukin-1; Kidney; Label; Ligands; Liver Fibrosis; Lung; MDR3 deficiency; Mediating; Modeling; Mus; Mutation; Myeloid Cells; Myofibroblast; PTPRC gene; Pathogenesis; Patients; Pharmacology; Phospholipids; Play; Population; Production; Proteins; RANTES; Recruitment Activity; Regulation; Reporting; Resistance; Role; Serum; Side; Signal Transduction; Skin; Source; Stimulus; TNF gene; Tamoxifen; Testing; Therapeutic; Therapeutic Effect; Transgenic Organisms; Translations; Transplantation; Type I Procollagen; Urokinase; base; care burden; collagenase; cytokine; fast food; fibrogenesis; immunoregulation; inhibitor/antagonist; injured; intrahepatic; liver development; liver injury; macrophage; major urinary proteins; migration; mutant; nonalcoholic steatohepatitis; overexpression; paracrine; pre-clinical; prevent; promoter; response; therapeutic evaluation; transcriptome sequencing; treatment choice

ABSTRACT: Bone marrow-derived fibrocytes, designated as CD45+ and Collagen Type I+ cells, were implicated in the pathogenesis of lung, skin, and kidney fibrosis due to their ability to differentiate into fibrogenic myofibroblasts. We have demonstrated that fibrocytes contribute to 4-6% of Col1a1-producing cells in the fibrotic liver1,2, suggesting that fibrocytes are not a significant source of ECM. Puzzled by these data, we continued investigating fibrocytes, and have now obtained strong preliminary data suggesting that genetic or pharmacological inhibition of fibrocytes attenuates development of liver fibrosis by 50%. The goal of this proposal is to determine the role of fibrocytes in the pathogenesis of liver fibrosis and develop therapeutic strategies of their inhibition. We hypothesize that targeting fibrocytes will inhibit liver fibrosis. The central hypothesis is that fibrocytes give rise to unique populations of fibrogenic myofibroblasts and pro-inflammatory myeloid cells that synergistically facilitate liver fibrosis by secreting TGF-1, TNF-, IL-11, CCL5 and other regulatory cytokines promoting M1 (and inhibiting anti-inflammatory M2) macrophages. To test this hypothesis, four complimentary AIMs have been developed: AIM 1. The role of fibrocytes in liver fibrosis will be determined in fibrocyte-ablated mice (versus wt mice) subjected to chronic toxic, cholestatic, and NASH liver injury. Genetic ablation of fibrocytes will be achieved by overexpression of Diphtheria toxin- (DTA) specifically in fibrocytes, and has not been previously reported. We anticipate that liver fibrosis of different etiologies is strongly attenuated in fibrocyte-ablated mice. AIM 2. We have developed a cell fate mapping approach to determine fibrocyte function(s), and the mechanism by which fibrocytes mediate liver fibrosis. Using a side-by- side comparison of wt and fibrocyte-ablated mice, we will determine if fibrocytes promote intrahepatic cytokine secretion, and regulate activation of M1 (vs M2) macrophages. We predict that fibrocytes play a major immunoregulatory role in liver fibrosis. AIM 3. The role of Col1a1 in regulation of fibrocyte biology will be studied by comparing wt and Col1a15'SL-mutant fibrocytes (with the “loss” of Col1a1 function) and Col11rr- mutant fibrocytes (with “gain” of Col1a1 function). The mechanism of Col1a1 signaling in fibrocytes, leading to their proliferation/activation, will be examined in primary and immortalized fibrocytes. We anticipate that Col1a1 regulates vital functions of fibrocytes via interaction with its ligand(s), such as DDR1 and 21 integrins. AIM 4. We test if therapeutic administration of Serum Amyloid P (SAP), a natural inhibitor of fibrocytes, can effectively attenuate liver fibrosis of different etiologies in mice, e.g. via inhibition of fibrocyte proliferation, cytokine production, and differentiation into myofibroblasts. We will analyze archived patient material to determine therapeutic potential of SAP for patients with NASH (the relationship between serum SAP, hepatic fibrocytes, and stage/progression of liver fibrosis). SAP might become a treatment of choice in patients with NASH.

摘要： 骨髓来源的纤维细胞，命名为CD 45+和I型胶原+细胞，参与了细胞凋亡。 由于它们分化成纤维化肌成纤维细胞的能力，肺、皮肤和肾纤维化的发病机制。 我们已经证明，在纤维化肝脏中，纤维细胞占Col 1a 1产生细胞的4-6% 1，2， 表明纤维细胞不是ECM的重要来源。这些数据让我们感到困惑， 研究纤维细胞，现在已经获得了强有力的初步数据，表明遗传或 纤维细胞的药理学抑制使肝纤维化的发展减弱约50%。的目标 该建议旨在确定纤维细胞在肝纤维化发病机制中的作用， 他们的抑制策略。我们假设靶向纤维细胞将抑制肝纤维化。中央 假设是纤维细胞产生独特的纤维化肌成纤维细胞群和促炎性细胞群， 骨髓细胞通过分泌TGF-β 1、TNF-α、IL-1 β 1、CCL 5和其他因子协同促进肝纤维化 促进M1（和抑制抗炎M2）巨噬细胞的调节细胞因子。为了检验这一假设， 已经开发了四种互补的AIM：AIM 1。纤维细胞在肝纤维化中的作用将被确定 在经受慢性毒性、胆汁淤积性和NASH肝损伤的纤维细胞消融小鼠（相对于野生型小鼠）中。 纤维细胞的基因消融将通过白喉毒素-β（DTA）的特异性过表达来实现， 纤维细胞，以前没有报道过。我们预期不同病因的肝纤维化是 在纤维细胞消融的小鼠中强烈减弱。AIM 2.我们已经开发了一种细胞命运映射方法， 确定纤维细胞功能和纤维细胞介导肝纤维化的机制。使用一个并排的- 通过比较WT和纤维细胞消融小鼠，我们将确定纤维细胞是否促进肝内细胞因子 分泌，并调节M1（vs M2）巨噬细胞的活化。我们预测，纤维细胞发挥主要作用， 免疫调节在肝纤维化中作用。AIM 3. Col 1a 1在纤维细胞生物学调节中的作用将是 通过比较野生型和Col 1a 15 'SL突变型纤维细胞（具有Col 1a 1功能的“丧失”）和Col 1a 11 rr， 突变型纤维细胞（Col 1a 1功能“获得”）。纤维细胞中Col 1a 1信号传导的机制，导致 它们的增殖/活化将在原代和永生化纤维细胞中进行检测。我们预计Col 1a 1 通过与其配体（如DDR 1和DDR2 β 1整联蛋白）的相互作用调节纤维细胞的重要功能。AIM 4. 我们测试了血清淀粉样蛋白P（SAP）（一种天然的纤维细胞抑制剂）的治疗性给药是否能有效地 减轻小鼠中不同病因的肝纤维化，例如通过抑制纤维细胞增殖、细胞因子 产生和分化成肌成纤维细胞。我们将分析存档的患者资料， SAP对NASH患者的治疗潜力（血清SAP，肝纤维细胞， 和肝纤维化的阶段/进展）。SAP可能成为NASH患者的治疗选择。