The role of alpha-v integrins on activated fibroblasts in pulmonary fibrosis
α-V整合素对肺纤维化中活化成纤维细胞的作用
基本信息
- 批准号:8970563
- 负责人:
- 金额:$ 4.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-07-14 至 2016-05-31
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAttenuatedAutomobile DrivingBindingBiological AssayBleomycinBlocking AntibodiesCarbon TetrachlorideCell SeparationCellsCharacteristicsClinicalCollagenDataDepositionDevelopmentDiseaseDisease ProgressionEpitheliumEventExtracellular MatrixFamilyFibroblastsFibrosisGeneticGoalsHealthcareHydroxyprolineIn VitroIntegrinsKidneyLaboratoriesLiteratureLiver FibrosisLungLung InflammationMediatingMediator of activation proteinModelingMusMyofibroblastOrganOrgan failurePDGFRB genePericytesPlatelet-Derived Growth Factor ReceptorPopulationProcessProductionPulmonary FibrosisReporterResearchResearch InfrastructureRoleSirius Red F3BSolidStaining methodStainsStructure of parenchyma of lungSystemTechniquesTherapeutic AgentsTissuesTransforming Growth FactorsUreteral obstructionbasecell typecytokinefibrogenesisin vivoindium-bleomycininhibitor/antagonistinsightinterestlung injurynew therapeutic targetprogenitorprotective effectpublic health relevancereceptorresearch studysmall moleculestemtargeted treatmenttool
项目摘要
DESCRIPTION (provided by applicant): Pulmonary fibrosis, the progressive and irreversible replacement of normal lung parenchyma with fibrotic tissues, is a major clinical burden when organ function is compromised. Treatment options for this disease are severely limited, underscoring the urgent need for therapies to attenuate and/or halt disease progression before organ failure. Characteristic features of pulmonary fibrosis include focal expansion of fibroblasts
and deposition of extracellular matrix, and activated fibroblasts are key executors of this process. TGF¿ is well known as a potent pro-fibrogenic cytokine driving lung fibrogenesis, and TGF¿ exerts much of its effects via interactions with integrins, a family of transmembrane receptors which consist of a ¿ and a ¿ subunit. Five integrins share the ¿v subunit, including ¿v¿1, ¿v¿3, ¿v¿5, ¿v¿6, and ¿v¿8, and all can activate TGF¿. While expression of ¿v¿6 is restricted to the epithelium, others are expressed in fibroblasts in multiple organs including lung Epithelium-restricted ¿v¿6 has been previously shown to spatially activate TGF¿, and this ¿v¿6-mediated TGF¿ activation has been demonstrated as an important player during lung fibrogenesis. Compared to ¿v¿6, the role of other ¿v integrins on fibroblasts in pulmonary fibrosis is less understood. Notably, our lab has recently found that in vivo deletion of ¿v integrins on pericytes/fibroblasts protects mice from fibrosis in several classic models, including
bleomycin-induced pulmonary fibrosis, unilateral ureteral obstruction-induced renal tubulointerstitial fibrosis, and carbon tetrachloride-induced hepatic fibrosis, which suggests that
¿v integrins on pericytes/fibroblasts are central mediators during fibrogenesis across solid organs. One goal of this proposed research aims to identify which sub-population of fibroblasts is critical for this ¿v integrin-mediated development of pulmonary fibrosis. Current literature implicates myofibroblasts, the subpopulation of fibroblasts expressing ¿-SMA, as the major activated fibroblasts during fibrogenesis; however, this idea remains controversial, and the specific role of myofibroblasts has not been rigorously investigated in vivo. As such, a mouse line in which myofibroblasts can be specifically targeted and genetically manipulated has been generated for this research, and whether loss of ¿v integrins on myofibroblasts protects mice from bleomycin-induced pulmonary fibrosis will be examined. In addition, by combining cell-type specific reporter mice and cell sorting techniques, the regulatory role of ¿v integrins on activate fibroblasts will be characterized. Finally, by using both genetic and pharmacologic tools, which one or more fibroblast ¿v integrin(s) is/are critical to contribute to pulmonary fibrosis in vivo wll be determined. Overall, this proposed research should define the role of myofibroblasts in vivo during lung fibrogenesis, and may unravel new therapeutic target(s) for the development of anti-fibrotic agents to treat pulmonary fibrosis.
描述(由申请人提供):肺纤维化是正常肺实质被纤维化组织进行性且不可逆的替代,当器官功能受到损害时,肺纤维化是一种主要的临床负担,这种疾病的治疗选择受到严重限制,这强调了迫切需要治疗。在器官衰竭之前减轻和/或阻止疾病进展。肺纤维化的特征包括成纤维细胞的局部扩张。
细胞外基质的沉积和沉积,而活化的成纤维细胞是该过程的关键执行者。众所周知,它是一种有效的促纤维化细胞因子,可驱动肺纤维化,而 TGF¿通过与整合素的相互作用发挥其大部分作用,整合素是一个跨膜受体家族,由 ¿和一个 ¿五个整合素共享 ¿ v 亚基,包括 ¿ v¿ 1, ¿ v¿ 3、?? v¿ 5、?? v¿ 6、和?? v¿ 8、一切都可以激活TGF¿ .虽然表达 ¿ v¿ 6 仅限于上皮,其他在多个器官的成纤维细胞中表达,包括肺上皮限制 ¿ v¿ 6 先前已被证明可以在空间上激活 TGF¿ ,这个 ¿ v¿ 6 介导的 TGF¿与 ¿ 相比,激活已被证明是肺纤维形成过程中的重要参与者。 v¿ 6、他人的角色v 整合素对肺纤维化中成纤维细胞的作用尚不清楚,值得注意的是,我们的实验室最近发现 ¿周细胞/成纤维细胞上的 v 整合素在几种经典模型中保护小鼠免受纤维化,包括
博来霉素诱发的肺纤维化、单侧输尿管梗阻诱发的肾小管间质纤维化和四氯化碳诱发的肝纤维化,这表明
¿周细胞/成纤维细胞上的 v 整合素是实体器官纤维发生过程中的中心介质,这项研究的一个目标是确定哪些成纤维细胞亚群对此至关重要。 v 整合素介导的肺纤维化发展目前的文献涉及肌成纤维细胞,即表达 ¿ -SMA,作为纤维形成过程中主要的活化成纤维细胞;然而,这一想法仍然存在争议,并且肌成纤维细胞的具体作用尚未在体内得到严格研究,因此,可以特异性靶向和基因操纵肌成纤维细胞的小鼠系。为此研究生成的,以及是否丢失 ¿此外,通过结合细胞类型报告特异性小鼠和细胞分选技术,将检查肌成纤维细胞上的 v 整合素保护小鼠免受博莱霉素诱导的肺纤维化的调节作用。最后,通过使用遗传和药理学工具,对激活的成纤维细胞上的 v 整合素进行表征,其中一种或多种成纤维细胞 ¿总的来说,整合素对于体内肺纤维化至关重要,这项研究应该明确肌成纤维细胞在肺纤维化过程中体内的作用,并可能揭示新的治疗靶点。抗纤维化药物可治疗肺纤维化。
项目成果
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Kai-Hui Sun其他文献
Kai-Hui Sun的其他文献
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{{ truncateString('Kai-Hui Sun', 18)}}的其他基金
The role of alpha-v integrins on activated fibroblasts in pulmonary fibrosis
α-v整合素对肺纤维化中活化成纤维细胞的作用
- 批准号:
8717259 - 财政年份:2014
- 资助金额:
$ 4.96万 - 项目类别:
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