Matricellular Signaling in Senescence and 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，必须严格调控。尽管细胞外基质的合成是伤口愈合的重要步骤，但过度的基质沉积可导致纤维化瘢痕的形成，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，基质沉积不足可能在伤口愈合受损中起作用，导致慢性不愈合伤口，这是糖尿病患者特别有风险的并发症。我们最近的研究表明，在正常的皮肤伤口愈合过程中，肉芽组织中的肌成纤维细胞被CCN 1驱动衰老，CCN 1是一种在伤口修复部位动态表达的基质细胞蛋白。CCN 1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CCN 1的突变敲入小鼠不会积累衰老细胞，并且在伤口中遭受加剧的纤维化。这些结果支持CCN 1依赖性细胞衰老是控制纤维化的程序性伤口愈合反应的假设。然而，这种纤维化控制机制在病理条件下可能变得失调，导致过度衰老细胞积聚并导致不愈合伤口的慢性化。我们将研究CCN 1诱导的细胞衰老在皮肤伤口愈合中的作用，具体目标有三个：目标1剖析CCN 1诱导的衰老的分子机制;目标2评估细胞衰老在伤口愈合过程中控制纤维化的作用;目标3阐明衰老细胞对慢性不愈合伤口的影响。总之，这些研究将推进我们对细胞衰老如何参与纤维化控制和伤口愈合慢性化的认识。

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.