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.

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