Fibrocytes regulate liver fibrosis

纤维细胞调节肝纤维化

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

抽象的：骨髓来源的纤维细胞，称为 CD45+ 和 I 型胶原蛋白+细胞，与肺、皮肤和肾纤维化的发病机制是由于它们能够分化为纤维化肌成纤维细胞。我们已经证明纤维细胞占纤维化肝脏中 4-6% 的 Col1a1 生成细胞1,2, 表明纤维细胞不是 ECM 的重要来源，我们对这些数据感到困惑，但继续说道。研究纤维细胞，现已获得强有力的初步数据，表明遗传或纤维细胞的药物抑制可将肝纤维化的发展减弱约 50%。该提案旨在确定纤维细胞在肝纤维化发病机制中的作用并开发治疗方法我们认为靶向纤维细胞会抑制肝纤维化。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细胞骨髓细胞通过分泌TGF-β1、TNF-α、IL-1β1、CCL5等协同促进肝纤维化调节细胞因子促进 M1（并抑制抗炎 M2）巨噬细胞为了检验这一假设，已开发出四个互补的 AIM： AIM 1. 将确定纤维细胞在肝纤维化中的作用在遭受慢性毒性、胆汁淤积和 NASH 肝损伤的纤维细胞消除小鼠（与野生型小鼠相比）中。纤维细胞的基因消融将通过白喉毒素-α (DTA) 的过度表达来实现，特别是在纤维细胞，并且之前没有报道过不同病因的肝纤维化。在纤维细胞消除的小鼠中强烈减弱。我们开发了一种细胞命运图谱方法。确定纤维细胞功能，以及纤维细胞介导肝纤维化的机制。野生型和纤维细胞消除小鼠的侧面比较，我们将确定纤维细胞是否促进肝内细胞因子我们预测纤维细胞发挥着主要作用。肝纤维化中的免疫调节作用 AIM 3. Col1a1 在纤维细胞生物学调节中的作用通过比较 wt 和 Col1a15'SL 突变型纤维细胞（Col1a1 功能“丧失”）和 Col1α1rr- 进行研究突变纤维细胞（“获得”Col1a1 功能）纤维细胞中 Col1a1 信号传导的机制，导致我们预计 Col1a1 将在原代和永生化纤维细胞中检查它们的增殖/激活。通过与其配体（例如 DDR1 和 21 AIM 4）相互作用来调节纤维细胞的重要功能。我们测试血清淀粉样蛋白 P (SAP)（纤维细胞的天然抑制剂）的治疗性给药是否可以有效减轻小鼠不同病因的肝纤维化，例如通过抑制纤维细胞增殖、细胞因子我们将分析存档的患者材料以确定。 SAP 对 NASH 患者的治疗潜力（血清 SAP、肝纤维细胞、 SAP 可能成为 NASH 患者的治疗选择。