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新兴的健康问题。这些愈合不良的伤口的一个共同特征是持续的炎症反应，并有促炎症的巨噬细胞积聚。这一建议的中心假设是糖尿病导致促炎单核细胞的过度产生，并降低了促愈合单核细胞的水平，这些单核细胞都导致糖尿病伤口愈合反应差。我们提出了一项涉及小鼠模型和人类患者的翻译研究，目的有三个：第一个目标是，我们将确定NLRP3炎症小体/IL-1β途径的持续活动是否会导致促炎单核细胞的过度产生和糖尿病患者的愈合障碍。在第二个目标中，我们将确定Nur77活性受损是否会降低促进单核细胞修复的水平，这些单核细胞有助于糖尿病患者的愈合受损。在第三个目标中，我们将进行一项信息丰富的双盲随机临床试验，以确定格列本脲局部治疗是否可以调节伤口渗透之前和/或之后的单核细胞亚群，并改善糖尿病的愈合。拟议的实验将提高对单核细胞亚群在糖尿病小鼠和人类受损愈合过程中的作用的了解，以及调节这些细胞产生的细胞内在和细胞外在机制。这些研究的影响在于最初转化为一种针对糖尿病患者单核细胞亚群的治疗方法，以诱导炎症消退，并刺激难以愈合的伤口的愈合反应。此外，这些研究可能导致开发包括监测血液单核细胞亚群作为细胞生物标记物的分析方法，以帮助选择有慢性伤口的糖尿病患者的治疗方案。

 DESCRIPTION (provided by applicant): Chronic wounds associated with diabetes are a burgeoning health problem in the United States. A common characteristic of these poorly healing wounds is a persistent inflammatory response, with accumulation of pro-inflammatory macrophages. The central hypothesis of this proposal is that diabetes induces overproduction of pro-inflammatory monocytes and reduces levels of pro-healing monocytes that each contribute to the poor healing responses in diabetic wounds. We propose a translational study involving both mouse models and human patients with three Specific Aims: in the first Aim, we will determine whether sustained activity of the NLRP3 inflammasome/IL-1β pathway results in overproduction of pro-inflammatory monocytes and impaired healing in diabetes. In the second Aim, we will determine whether impaired activity of Nur77 reduces levels of pro-healing monocytes contributing to impaired healing in diabetes. In the third Aim, we will perform an informative pilot double-blinded, randomized clinical trial to determine whether topical treatment with glyburide can modulate monocyte subsets prior to and/or after wound infiltration and improve healing in diabetes. The proposed experiments will improve knowledge of the role of monocyte subsets during impaired healing in diabetic mice and humans along with cell-intrinsic and cell-extrinsic mechanisms that regulate production of these cells. The impact of these studies lies in the initial translation to a therapy that targets monocyte subsets in diabetic patients to induce resolution of inflammation and stimulate healing responses in hard-to-heal wounds. In addition, the studies could lead to development of assays that involve monitoring blood monocyte subsets as cellular biomarkers to aid in the selection of treatment options for diabetic patients with chronic wounds.