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,必须严格监管。虽然细胞外基质的合成是伤口愈合的重要步骤,但过多的基质沉积可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,缺乏基质沉积可在伤口愈合受损中发挥作用,导致慢性不愈合伤口,这是糖尿病患者特别危险的并发症。我们最近的研究表明,在正常皮肤伤口愈合过程中,肉芽组织中的肌成纤维细胞被CCN1驱动进入衰老,CCN1是一种在伤口修复部位动态表达的基质细胞蛋白。CCN1通过整合素介导的新途径诱导细胞衰老,并激活衰老细胞特有的抗纤维化遗传程序的表达。表达衰老缺陷的CCN1的突变敲入小鼠不会积累衰老细胞,并且在伤口中遭受加重的纤维化。这些结果支持了ccn1依赖性细胞衰老是控制纤维形成的程序性伤口愈合反应的假设。然而,在病理条件下,这种纤维化控制机制可能会失控,导致过度的衰老细胞积累,并导致伤口不愈合的慢性。我们将从三个方面探讨ccn1诱导的细胞衰老在皮肤创面愈合中的作用:目的1解剖ccn1诱导衰老的分子机制;目的2评估细胞衰老在伤口愈合过程中控制纤维化的作用;和Aim 3阐明衰老细胞对慢性不愈合伤口的作用。总之,这些研究将推进我们对细胞衰老如何参与纤维化控制和伤口愈合的慢性的认识。
项目成果
期刊论文数量(0)
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LESTER F LAU其他文献
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{{ truncateString('LESTER F LAU', 18)}}的其他基金
Integrin-mediated matricellular signaling in experimental colitis
实验性结肠炎中整合素介导的基质细胞信号传导
- 批准号:
9912136 - 财政年份:2017
- 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
- 批准号:
8464008 - 财政年份:2011
- 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
- 批准号:
8185672 - 财政年份:2011
- 资助金额:
$ 35.87万 - 项目类别:
The Matricellular Protein CCN1 in Wound Healing
基质细胞蛋白 CCN1 在伤口愈合中的作用
- 批准号:
10170298 - 财政年份:2011
- 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
- 批准号:
8654259 - 财政年份:2011
- 资助金额:
$ 35.87万 - 项目类别:
Regulation of TNF-alpha by Integrin-Mediated Matrix Signaling
整合素介导的基质信号传导对 TNF-α 的调节
- 批准号:
7929741 - 财政年份:2009
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$ 35.87万 - 项目类别:
Integrin-Mediated Matrix Signaling in Liver Fibrosis
肝纤维化中整合素介导的基质信号传导
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8668999 - 财政年份:2007
- 资助金额:
$ 35.87万 - 项目类别:
Integrin-Matrix Interaction in Cardiovascular Development
心血管发育中的整合素-基质相互作用
- 批准号:
7436256 - 财政年份:2007
- 资助金额:
$ 35.87万 - 项目类别:
Regulation of TNF-alpha by Integrin-Mediated Matrix Signaling
整合素介导的基质信号传导对 TNF-α 的调节
- 批准号:
7860286 - 财政年份:2007
- 资助金额:
$ 35.87万 - 项目类别:
Integrin-Matrix Interaction in Cardiovascular Development
心血管发育中的整合素-基质相互作用
- 批准号:
7211033 - 财政年份:2007
- 资助金额:
$ 35.87万 - 项目类别:
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