The Role of ERK5 Signalling Macrophage Behaviour During Wound Healing

项目描述：（最多4000字）组织修复和再生需要损伤部位的伤口常驻细胞和对受伤组织作出反应并被招募的远端细胞的细胞行为发生戏剧性和协调的变化。在过去的十年中，炎症细胞对伤口愈合的影响已经被证明是非常显著的，因为它们可以促进或抑制伤口愈合。发现控制炎症细胞行为的潜在机制对于控制这些细胞以获得治疗益处至关重要。为了了解正常过程是如何调控的，将正常过程与患病过程进行比较通常是很有指导意义的。糖尿病患者和动物模型的伤口愈合严重受损，经常发展为慢性伤口。发现炎症细胞功能失调，抑制伤口愈合。具体来说，巨噬细胞是伤口中关键的炎症介质，并在伤口内对动态环境线索做出反应。持续炎症表型的巨噬细胞浸润上调与伤口愈合受损相关，但巨噬细胞在健康和受损伤口愈合不同阶段的影响尚不完全清楚。一个特别感兴趣的信号通路是细胞外信号相关激酶5 （ERK5）。已知ERK5调节多种细胞过程，包括增殖、迁移、血管生成以及炎症。特别是ERK5控制肿瘤中巨噬细胞的极化和行为。鉴于ERK5在巨噬细胞生物学中在癌症中的关键作用，这有可能转化为巨噬细胞在其他情况下扮演关键角色，如伤口愈合反应。具体来说，本项目将研究小鼠模型角化细胞ERK5基因消融对伤口愈合和炎症的作用，并在体外和体内模型中通过一种新的药物干预来评估这一靶点的可翻译性。

Project Description: (maximum of 4,000 characters)Tissue repair and regeneration require dramatic and coordinated changes in cell behaviour in both wound-resident cells at the site of injury and in distant cells that respond to and are recruited to the injured tissue. In the last decade, the influence of inflammatory cells on wound healing has been shown to be highly significant, as they can function to promote or inhibit wound healing. Discovering the underlying mechanisms controlling the behaviour of inflammatory cells is pivotal to controlling these cells for therapeutic benefit. It is often very instructive to compare normal processes with diseased processes in order to understand how that process is regulated. Diabetic patients and animal models have severely impaired wound healing and often develop chronic wounds. The inflammatory cells found are dysfunctional and inhibit the wound healing. Specifically, macrophages are critical inflammatory mediators in wounds, and adopt behaviours in response to dynamic environmental cues within the wound. Upregulated macrophage infiltration with a persistent inflammatory phenotype correlates with impaired wound healing, yet the influence of macrophages during the different stages of healthy and impaired wound healing is not fully understood. One particular signalling pathway of interest is extracellular signal related kinase 5 (ERK5). ERK5 is known to regulate a diverse set of cellular processes including proliferation, migration and angiogenesis as well as inflammation. In particular ERK5 controls the polarization and behaviour of macrophages in tumours. Given the pivotal role of ERK5 in macrophage biology in cancer, there is potential for this to translate to other scenarios where macrophages are key players such as wound healing responses. Specifically, this project will investigate the role that genetic ablation of ERK5 in keratinocytes of murine models has on wound healing and inflammation and evaluate the translatability of this target with a novel pharmacological intervention in both in vitro and in vivo models.