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严重的健康问题。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。慢性创面表现出失调的炎症反应，巨噬细胞和炎性细胞因子持续聚集。我们建议进行一项翻译研究，以解决我们的中心假设，即从促炎细胞表型到促进愈合的巨噬细胞表型的受损转换是糖尿病伤口愈合反应较差的原因，而诱导巨噬细胞转换表型将促进愈合。这项研究由三个具体目标组成：第一个目标，我们将确定炎症小体的持续活动是否促进了糖尿病小鼠伤口向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体增殖物激活受体-3途径的活性受损是否阻止糖尿病小鼠伤口从促炎向促愈合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损害了从促炎表型到促进愈合的MP表型的转换，从而损害了慢性伤口的愈合。拟议的实验将提高对巨噬细胞表型在糖尿病伤口愈合障碍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调节慢性伤口巨噬细胞表型的治疗方法，以诱导炎症消退，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创面的MP表型是否可以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.