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
- 来源:
- 关键词:5&apos Untranslated RegionsAblationAlpha CellAmyloidAnti-Inflammatory AgentsAnti-inflammatoryArchivesAttenuatedBiologyBone MarrowCellsChronicCirrhosisClinical TrialsCollagenCollagen Type IDDR1 geneDataDepositionDevelopmentDietDiphtheria ToxinEnhancersEtiologyExtracellular Matrix ProteinsFibroblast Growth FactorFibrosisGeneticGoalsHealthcareHematopoieticHepaticITGAM geneInflammationInflammatoryInjuryInjury to LiverIntegrinsInterleukin-1KidneyLabelLigandsLiver FibrosisLungMDR3 deficiencyMediatingModelingMusMutationMyeloid CellsMyofibroblastPTPRC genePathogenesisPatientsPharmacologyPhospholipidsPlayPopulationProductionProteinsRANTESRecruitment ActivityRegulationReportingResistanceRoleSerumSideSignal TransductionSkinSourceStimulusTNF geneTamoxifenTestingTherapeuticTherapeutic EffectTransgenic OrganismsTranslationsTransplantationType I ProcollagenUrokinasebasecare burdencollagenasecytokinefast foodfibrogenesisimmunoregulationinhibitor/antagonistinjuredintrahepaticliver developmentliver injurymacrophagemajor urinary proteinsmigrationmutantnonalcoholic steatohepatitisoverexpressionparacrinepre-clinicalpreventpromoterresponsetherapeutic evaluationtranscriptome sequencingtreatment 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-11, 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 Col11rr-
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 21 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.
文摘:
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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:
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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