The Role of ERK5 Signalling Macrophage Behaviour During Wound Healing

点击翻译按钮获取中文摘要

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.