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:
  • 金额:
    $ 34.88万
  • 依托单位:
  • 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

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.
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项目成果

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Tatiana Kisseleva其他文献

Tatiana Kisseleva的其他文献

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{{ truncateString('Tatiana Kisseleva', 18)}}的其他基金

The role of IL-17 signaling in alcohol-induced HCC
IL-17 信号在酒精诱导的 HCC 中的作用
  • 批准号:
    10299157
  • 财政年份:
    2021
  • 资助金额:
    $ 34.88万
  • 项目类别:
The role of IL-17 signaling in alcohol-induced HCC
IL-17 信号在酒精诱导的 HCC 中的作用
  • 批准号:
    10463697
  • 财政年份:
    2021
  • 资助金额:
    $ 34.88万
  • 项目类别:
Novel IL-23 inhibitor for the treatment of alcohol associated liver disease
用于治疗酒精相关性肝病的新型 IL-23 抑制剂
  • 批准号:
    10482350
  • 财政年份:
    2020
  • 资助金额:
    $ 34.88万
  • 项目类别:
Novel IL-23 inhibitor for the treatment of alcohol associated liver disease
用于治疗酒精相关性肝病的新型 IL-23 抑制剂
  • 批准号:
    10266186
  • 财政年份:
    2020
  • 资助金额:
    $ 34.88万
  • 项目类别:
Preclinical Models Core
临床前模型核心
  • 批准号:
    10617220
  • 财政年份:
    2019
  • 资助金额:
    $ 34.88万
  • 项目类别:
The Role of Portal Fibroblasts in Cholestatic Liver Fibrosis
门静脉成纤维细胞在胆汁淤积性肝纤维化中的作用
  • 批准号:
    10441586
  • 财政年份:
    2014
  • 资助金额:
    $ 34.88万
  • 项目类别:
Inactivation of Hepatic Stellate Cells During Reversal of Liver Fibrosis
肝纤维化逆转过程中肝星状细胞失活
  • 批准号:
    8694267
  • 财政年份:
    2014
  • 资助金额:
    $ 34.88万
  • 项目类别:
The Role of Portal Fibroblasts in Cholestatic Liver Fibrosis
门静脉成纤维细胞在胆汁淤积性肝纤维化中的作用
  • 批准号:
    10312314
  • 财政年份:
    2014
  • 资助金额:
    $ 34.88万
  • 项目类别:
Epigenetics of human Hepatic Stellate Cells (HSCs) in NASH
NASH 中人肝星状细胞 (HSC) 的表观遗传学
  • 批准号:
    10367096
  • 财政年份:
    2014
  • 资助金额:
    $ 34.88万
  • 项目类别:
Inactivation of Hepatic Stellate Cells During Reversal of Liver Fibrosis
肝纤维化逆转过程中肝星状细胞失活
  • 批准号:
    9271180
  • 财政年份:
    2014
  • 资助金额:
    $ 34.88万
  • 项目类别:

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