The Role of ERK5 Signalling Macrophage Behaviour During Wound Healing

ERK5 信号传导巨噬细胞行为在伤口愈合过程中的作用

• 批准号: 1916346
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1916346
• 关键词: Role; ERK5; Signalling; Macrophage; Behaviour

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.

项目描述：（最多 4,000 个字符）组织修复和再生需要损伤部位的伤口驻留细胞和对受伤组织做出反应并被招募到受伤组织的远处细胞的细胞行为发生显着且协调的变化。在过去的十年中，炎症细胞对伤口愈合的影响已被证明是非常重要的，因为它们可以起到促进或抑制伤口愈合的作用。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效果至关重要。将正常过程与患病过程进行比较通常非常有启发性，以便了解该过程是如何调节的。糖尿病患者和动物模型的伤口愈合严重受损，并且经常形成慢性伤口。发现的炎症细胞功能失调并抑制伤口愈合。具体来说，巨噬细胞是伤口中关键的炎症介质，并采取响应伤口内动态环境线索的行为。具有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。一种特别令人感兴趣的信号传导途径是细胞外信号相关激酶 5 (ERK5)。众所周知，ERK5 可以调节多种细胞过程，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 在癌症巨噬细胞生物学中的关键作用，这有可能转化为巨噬细胞发挥关键作用的其他场景，例如伤口愈合反应。具体来说，该项目将研究小鼠模型角质形成细胞中 ERK5 基因消融对伤口愈合和炎症的作用，并通过体外和体内模型中的新型药理学干预来评估该靶标的可转化性。