Biliary Epithelial Cell-derived SDF-1a in Hepatic Fibrogenesis and Inflammation
胆管上皮细胞衍生的 SDF-1a 在肝纤维形成和炎症中的作用
基本信息
- 批准号:8422998
- 负责人:
- 金额:$ 4.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-01-17 至 2015-01-16
- 项目状态:已结题
- 来源:
- 关键词:AnimalsBile AcidsBiliaryBone MarrowCXCL12 geneCXCR4 ReceptorsCXCR4 geneCellsCellular biologyCessation of lifeCharacteristicsChemotaxisChronicCirrhosisCoculture TechniquesCollagenEnzyme-Linked Immunosorbent AssayEpithelial CellsEtiologyFibrosisGene DeliveryGoalsHematopoietic stem cellsHepaticHepatic FibrogenesisHepatic Stellate CellHepatitis C virusHistopathologic GradeHydroxyprolineHypoxiaIn VitroInfiltrationInflammationInflammatoryInflammatory InfiltrateInjuryLigationLinkLiverLiver FailureLiver FibrosisLiver diseasesLymphocyteMeasuresMediatingMessenger RNAModelingMolecularMusNeoplasm MetastasisOrgan DonorPathogenesisPathway interactionsPatientsPlasmaPlasma ProteinsPlasmidsProcessProteinsReactive Oxygen SpeciesRoleSiteStagingStaining methodStainsStromal Cell-Derived Factor 1Stromal CellsSystemTestingTissuesUp-RegulationWestern Blottingangiogenesisbasebile ductchemokinefibrogenesisinflammatory markerinhibitor/antagonistinjuredliver injuryliver transplantationmigrationmouse modelneutralizing antibodyplatelet-derived growth factor BBpublic health relevanceregenerativesmall moleculestellate cell
项目摘要
DESCRIPTION (provided by applicant): Regardless of the etiology, fibrosis is the final common pathway for chronic liver injury and failure. Fibrosis with subsequent complications of cirrhosis results in the death of patients with end stage liver disease if liver transplantation is not performed. As a result of the liver's unique regenerative capacity, progression to severe complications is a slow process often spanning decades. Slowing the progression of fibrosis will therefore have significant long-term benefit and mandates a greater understanding of the molecular and cellular basis of hepatic fibrosis. Stromal cell derived factor-11 (SDF-11/CXCL12), is a chemokine that promotes retention of hematopoietic stem cells in the bone marrow, cancer metastasis, angiogenesis and migration of lymphocytes to sites of injury through interactions with its receptor, CXCR4. Hepatic stellate cell (HSC) activation is central feature of fibrosis in all forms of chronic liver injury and we have established that HSCs express functional CXCR4 receptor and its engagement by SDF-11 induces cellular activation, collagen I expression, and proliferation, providing a direct link between SDF-11 and liver disease pathogenesis. The hepatic expression of SDF-11 is predominantly localized to biliary epithelial cells (BECs). During liver injury, BECs undergo marked proliferation associated with elevated hepatic and plasma protein levels of SDF-11. Importantly, plasma levels of SDF-11 correlate with increased liver fibrosis in patients with chronic HCV, indicating an important relationship to fibrosis. Interestingly, nearly all lymphocyte infiltration into the injured liver is localized to the SDF-11-expressing periportal region, indicating an additional role for SDF-11 in lymphocyte migration to the liver. Therefore I propose that BEC-derived SDF-11 promotes fibrosis by activation of hepatic stellate cells and mediates hepatic inflammation via recruitment of inflammatory cells. The aims of this proposal are: 1) To determine the importance of the SDF-11/CXCR4 axis in promoting hepatic fibrosis and inflammation in mechanistically distinct mouse models of liver injury (BDL and CCl4) by blocking the SDF-11/CXCR4 (SDF-11 neutralizing antibody or CXCR4 small molecule inhibitor). Fibrosis will be assessed using Sirius Red staining for collagen/morphometric analysis, hydroxyproline quantitation, and qRT-PCR for fibrogenic markers and inflammation will be assessed by histologic grading and characteristics of inflammatory infiltrate will be analyzed using FACS for cell-specific markers. 2) To evaluate the factors leading to increased SDF-11 expression by BECs by measuring mRNA and protein levels of SDF-11 in culture stimulated BECs and to determine whether BEC produced SDF-11 is sufficient to promote HSC biology in in vitro co-culture models.
描述(由申请人提供):无论病因如何,纤维化是慢性肝损伤和衰竭的最终共同途径。如果不进行肝移植,纤维化和随后的肝硬化并发症会导致终末期肝病患者死亡。由于肝脏独特的再生能力,严重并发症的进展是一个缓慢的过程,往往跨越几十年。因此,减缓纤维化的进展将具有显著的长期益处,并要求更好地理解肝纤维化的分子和细胞基础。 基质细胞衍生因子-11(SDF-11/CXCL 12)是一种趋化因子,其通过与其受体CXCR 4相互作用促进造血干细胞在骨髓中的保留、癌症转移、血管生成和淋巴细胞向损伤部位的迁移。肝星状细胞(HSC)活化是所有形式慢性肝损伤中纤维化的中心特征,我们已经确定HSC表达功能性CXCR 4受体,其与SDF-11的结合诱导细胞活化、胶原蛋白I表达和增殖,提供了SDF-11与肝病发病机制之间的直接联系。 SDF-11的肝脏表达主要定位于胆管上皮细胞(BEC)。在肝损伤期间,BEC经历与升高的肝和血浆SDF-11蛋白水平相关的显著增殖。重要的是,SDF-11的血浆水平与慢性HCV患者的肝纤维化增加相关,表明与纤维化的重要关系。有趣的是,几乎所有的淋巴细胞浸润到损伤的肝脏都位于SDF-11表达的门静脉周围区域,表明SDF-11在淋巴细胞迁移到肝脏中的额外作用。 因此,我认为BEC衍生的SDF-11通过激活肝星状细胞促进纤维化,并通过募集炎性细胞介导肝脏炎症。本提案的目的是:1)通过阻断SDF-11/CXCR 4(SDF-11中和抗体或CXCR 4小分子抑制剂),确定SDF-11/CXCR 4轴在机制不同的肝损伤小鼠模型(BDL和CCl 4)中促进肝纤维化和炎症的重要性。将使用天狼星红染色进行胶原蛋白/形态测定分析、羟脯氨酸定量和qRT-PCR进行纤维化评估,并通过组织学分级评估炎症,并使用FACS分析细胞特异性标志物的炎性浸润特征。2)通过测量培养物刺激的BEC中SDF-11的mRNA和蛋白水平,评价导致BEC表达SDF-11增加的因素,并确定BEC产生的SDF-11是否足以促进体外共培养模型中HSC的生物学。
项目成果
期刊论文数量(0)
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Yedidya Saiman其他文献
Yedidya Saiman的其他文献
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{{ truncateString('Yedidya Saiman', 18)}}的其他基金
Biliary Epithelial Cell-derived SDF-1a in Hepatic Fibrogenesis and Inflammation
胆管上皮细胞衍生的 SDF-1a 在肝纤维形成和炎症中的作用
- 批准号:
8055098 - 财政年份:2011
- 资助金额:
$ 4.72万 - 项目类别:
Biliary Epithelial Cell-derived SDF-1a in Hepatic Fibrogenesis and Inflammation
胆管上皮细胞衍生的 SDF-1a 在肝纤维形成和炎症中的作用
- 批准号:
8585054 - 财政年份:2011
- 资助金额:
$ 4.72万 - 项目类别:
Biliary Epithelial Cell-derived SDF-1a in Hepatic Fibrogenesis and Inflammation
胆管上皮细胞衍生的 SDF-1a 在肝纤维形成和炎症中的作用
- 批准号:
8223125 - 财政年份:2011
- 资助金额:
$ 4.72万 - 项目类别:
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