Macrophage Phenotype and Impaired Wound Healing

描述（由申请人提供）：与糖尿病相关的慢性伤口在美国是一个重要的健康问题。尽管这些愈合不良的伤口具有社会经济影响，但愈合受损的根本原因尚不清楚，有效的治疗方法仍然难以捉摸。慢性伤口表现出失调的炎症反应，伴有巨噬细胞和炎症细胞因子的持续积累。我们提出了一项转化研究，以解决我们的中心假设，即从促炎到促愈合的巨噬细胞表型的受损转换导致糖尿病伤口愈合反应差，诱导巨噬细胞转换表型将改善愈合。本研究由三个特定目标组成：在第一个目标中，我们将确定炎症小体（炎症调节的关键控制点）的持续活动是否会促进糖尿病小鼠伤口中促炎巨噬细胞表型的偏向。在第二个目标中，我们将确定抗炎过氧化物酶体增殖物激活受体-3途径活性受损是否会阻断糖尿病小鼠伤口中从促炎到促愈合的Mp表型的转换。在第三个目标中，我们将确定糖尿病伤口环境是否会损害从促炎到促愈合的Mp表型的转换，从而损害慢性伤口的愈合。提出的实验将提高对巨噬细胞表型在糖尿病伤口愈合受损中的作用和调节的认识。如果实验支持我们的中心假设，未来的研究将集中在开发慢性伤口中调节巨噬细胞表型的治疗方法，以诱导炎症的消退并刺激这些难以愈合的伤口的愈合反应。此外，我们将确定监测慢性伤口中的Mp表型是否可用于帮助选择目前可用于靶向炎症的治疗方案。

DESCRIPTION (provided by applicant): Chronic wounds associated with diabetes represent a significant health problem in the United States. Despite the socioeconomic impact of these poorly healing wounds, the underlying causes of impaired healing are not well understood and effective treatments remain elusive. Chronic wounds exhibit a dysregulated inflammatory response, with persistent accumulation of macrophages and inflammatory cytokines. We propose a translational study to address our central hypothesis that an impaired switch from pro-inflammatory to pro-healing macrophage phenotypes contributes to the poor healing responses in diabetic wounds and that inducing macrophages to switch phenotype will improve healing. The study is composed of three Specific Aims: in the first Aim, we will determine whether sustained activity of the inflammasome, a critical control point in the regulation of inflammation, promotes a bias towards the pro-inflammatory macrophage phenotype in wounds of diabetic mice. In the second Aim, we will determine whether impaired activity of the anti-inflammatory peroxisome proliferator- activated receptor-3 pathway blocks the switch from pro-inflammatory to pro-healing Mp phenotypes in wounds of diabetic mice. In the third Aim, we will determine whether the diabetic wound environment impairs the switch from pro-inflammatory to pro-healing Mp phenotypes, which impairs healing of chronic wounds. The proposed experiments will improve knowledge of the role and regulation of macrophage phenotypes in the impaired healing of diabetic wounds. If the experiments support our central hypothesis, future studies will be focused on developing therapies that modulate macrophage phenotype in chronic wounds to induce resolution of inflammation and stimulate healing responses in these hard-to-heal wounds. In addition, we will determine whether monitoring Mp phenotype in chronic wounds can be used to aid in the selection of treatment options that are currently available for targeting inflammation.