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：
8185672
负责人：
LESTER F LAU
金额：
$ 35.78万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
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：
https://reporter.nih.gov/project-details/8185672
关键词：
Adhesions Adult Affect Amputation Binding Binding Sites Cardiovascular system Cell Adhesion Cell Aging Cell Proliferation Cell physiology Cell surface Cells Cessation of life Characteristics Chronic Cicatrix Complex Complication Congestive Heart Failure Cutaneous Deposition Development Diabetes Mellitus Diabetic wound Embryo Event Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Fibrosis Genes Genetic Programming Granulation Tissue Heart Heparan Sulfate Proteoglycan Hepatic Stellate Cell Human Impaired wound healing Individual Inflammation Injury Integrins Knowledge Lead Liver Liver Cirrhosis Lung Lung diseases Mammals Maps Mediating Molecular Morbidity - disease rate Mus Myocardial Myofibroblast Organ Organ failure Pathology Pathway interactions Patients Play Process Proteins Public Health Pulmonary Fibrosis Reporting Research Resolution Risk Role Signal Transduction Site Structure Testing Therapeutic Intervention Tissues Virus Diseases Wound Healing base diabetic diabetic patient fibrogenesis migration mortality mouse model mutant new therapeutic target novel novel therapeutics programs receptor repaired response senescence wound

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. PUBLIC HEALTH RELEVANCE: Wound healing is a complex, multi-step process that must be tightly regulated. Excessive deposition of extracellular matrix often occurs in association with chronic injuries, and may result in fibrosis with serious consequences such as liver cirrhosis and pulmonary fibrosis. Impaired wound healing can also lead to chronic non-healing wounds, which may require amputations. This proposal seeks to understand the role of cellular senescence in wound healing, which may underlie the pathologies of both fibrotic wound healing and chronic non-healing wounds. We anticipate that our results will prompt new therapeutic strategies that may reduce the morbidity and mortality associated with impaired wound healing.

描述（由申请人提供）：哺乳动物伤口愈合是一个复杂的、多步骤的过程，必须受到严格监管。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，基质沉积不足可能会导致伤口愈合受损，导致慢性不愈合伤口，而糖尿病患者特别容易出现这种并发症。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（一种在伤口修复部位动态表达的基质细胞蛋白）驱动进入衰老状态。 CCN1 通过一种新的整合素介导的途径诱导细胞衰老，并激活衰老细胞特有的抗纤维化遗传程序的表达。表达衰老缺陷型CCN1的突变敲入小鼠不会积累衰老细胞，并且伤口中的纤维化会加剧。这些结果支持这样的假设：CCN1 依赖性细胞衰老是一种控制纤维发生的程序性伤口愈合反应。然而，这种纤维化控制机制在病理条件下可能会失调，导致衰老细胞过度积累并导致伤口长期不愈合。我们将从三个具体目标研究CCN1诱导的细胞衰老在皮肤伤口愈合中的作用：目标1剖析CCN1诱导衰老的分子机制；目标 2 评估细胞衰老在控制伤口愈合过程中纤维化中的作用；目标 3 阐明衰老细胞对慢性不愈合伤口的影响。总之，这些研究将增进我们对细胞衰老如何参与纤维化控制和伤口愈合慢性的了解。公共卫生相关性：伤口愈合是一个复杂的、多步骤的过程，必须受到严格监管。细胞外基质的过度沉积往往与慢性损伤有关，并可能导致纤维化，造成肝硬化和肺纤维化等严重后果。伤口愈合受损还会导致慢性不愈合伤口，可能需要截肢。该提案旨在了解细胞衰老在伤口愈合中的作用，这可能是纤维化伤口愈合和慢性不愈合伤口病理学的基础。我们预计我们的结果将促进新的治疗策略，从而降低与伤口愈合受损相关的发病率和死亡率。