Matricellular Signaling in Senescence and Wound Healing
衰老和伤口愈合中的基质细胞信号传导
基本信息
- 批准号:8309979
- 负责人:
- 金额:$ 35.87万
- 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:2011-08-01 至 2016-04-30
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsAdultAffectAmputationBindingBinding SitesCardiovascular systemCell AdhesionCell AgingCell ProliferationCell physiologyCell surfaceCellsCessation of lifeCharacteristicsChronicCicatrixComplexComplicationCongestive Heart FailureCutaneousDepositionDevelopmentDiabetes MellitusDiabetic woundEmbryoEventExtracellular MatrixExtracellular Matrix ProteinsFibroblastsFibrosisGenesGenetic ProgrammingGranulation TissueHeartHeparan Sulfate ProteoglycanHepatic Stellate CellHumanImpaired wound healingIndividualInflammationInjuryIntegrinsKnowledgeLeadLiverLiver CirrhosisLungLung diseasesMammalsMapsMediatingMolecularMorbidity - disease rateMusMyocardialMyofibroblastOrganOrgan failurePathologyPathway interactionsPatientsPlayProcessProteinsPublic HealthPulmonary FibrosisReportingResearchResolutionRiskRoleSignal TransductionSiteStructureTestingTherapeutic InterventionTissuesVirus DiseasesWound Healingbasediabeticdiabetic patientfibrogenesismigrationmortalitymouse modelmutantnew therapeutic targetnovelnovel therapeuticsprogramsreceptorrepairedresponsesenescencetissue repairwound
项目摘要
DESCRIPTION (provided by applicant): Mammalian wound healing is a complex, multi-step process that must be tightly regulated. Whereas synthesis of extracellular matrix is an essential step in wound healing, excessive matrix deposition can lead to the formation of fibrotic scars, resulting in compromised structure and function of the affected organ or tissue. Some of the deleterious consequences of fibrotic wound healing include liver cirrhosis, pulmonary fibrosis, and congestive heart failure. On the other hand, deficient matrix deposition can play a role in impaired wound healing leading to chronic non-healing wounds, a complication for which patients with diabetes are at particular risk. Our recent studies have revealed that in the course of normal cutaneous wound healing, myofibroblasts in the granulation tissue are driven into senescence by CCN1, a matricellular protein that is dynamically expressed at sites of wound repair. CCN1 induces cellular senescence through a novel integrin-mediated pathway, and activates the expression of an anti-fibrotic genetic program characteristic of senescent cells. Mutant knockin mice that express a senescence-defective CCN1 do not accumulate senescent cells and suffer exacerbated fibrosis in wounds. These results support the hypothesis that CCN1-dependent cellular senescence is a programmed wound healing response that controls fibrogenesis. However, this mechanism of fibrosis control may become deregulated under pathological conditions, leading to excessive senescent cell accumulation and contributing to the chronicity of non-healing wounds. We will investigate the role of CCN1-induced cellular senescence in cutaneous wound healing in three specific aims: Aim 1 dissects the molecular mechanism of CCN1-induced senescence; Aim 2 evaluates the role of cellular senescence in controlling fibrosis during wound healing; and Aim 3 elucidates the effects of senescent cells on chronic non-healing wounds. Together, these studies will advance our knowledge of how cellular senescence participates in fibrosis control and chronicity in wound healing.
描述(由申请人提供):哺乳动物伤口愈合是一个复杂的多步骤过程,必须严格调节。虽然细胞外基质的合成是伤口愈合的重要步骤,但过度的基质沉积会导致纤维化疤痕的形成,从而导致受影响器官或组织的结构和功能受损。纤维化伤口愈合的一些有害后果包括肝硬化,肺纤维化和充血性心力衰竭。另一方面,缺乏基质沉积可以在伤口愈合受损中发挥作用,导致慢性非治疗伤口,这是糖尿病患者特别风险的并发症。我们最近的研究表明,在正常的皮肤伤口愈合过程中,肉芽组织中的肌纤维细胞被CCN1驱动到衰老,CCN1是一种在伤口修复部位动态表达的母细胞蛋白。 CCN1通过一种新型整联蛋白介导的途径诱导细胞衰老,并激活衰老细胞的抗纤维化遗传程序特征的表达。表达衰老缺陷CCN1的突变敲蛋白小鼠不会累积衰老细胞,并在伤口中遭受恶化的纤维化。这些结果支持以下假设:CCN1依赖性细胞衰老是控制纤维发生的编程伤口愈合反应。然而,这种纤维化控制的机制可能在病理条件下引起管制,导致过度衰老的细胞积累并导致非愈合伤口的慢性性。我们将研究CCN1诱导的细胞衰老在三个特定目标中的皮肤伤口愈合中的作用:AIM 1解剖CCN1诱导的衰老的分子机制; AIM 2评估细胞衰老在控制伤口愈合过程中纤维化中的作用; AIM 3阐明了衰老细胞对慢性非治疗伤口的影响。这些研究将共同提高我们对细胞衰老如何参与纤维化控制和慢性伤口愈合的了解。
项目成果
期刊论文数量(0)
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LESTER F LAU其他文献
LESTER F LAU的其他文献
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Integrin-mediated matricellular signaling in experimental colitis
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- 资助金额:
$ 35.87万 - 项目类别:
Matricellular Signaling in Senescence and Wound Healing
衰老和伤口愈合中的基质细胞信号传导
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8464008 - 财政年份:2011
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$ 35.87万 - 项目类别:
Matricellular Signaling in Senescence and Wound Healing
衰老和伤口愈合中的基质细胞信号传导
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$ 35.87万 - 项目类别:
The Matricellular Protein CCN1 in Wound Healing
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- 批准号:
10170298 - 财政年份:2011
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$ 35.87万 - 项目类别:
Matricellular Signaling in Senescence and Wound Healing
衰老和伤口愈合中的基质细胞信号传导
- 批准号:
8654259 - 财政年份:2011
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Regulation of TNF-alpha by Integrin-Mediated Matrix Signaling
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