JAK/STAT Regulation of Macrophage-mediated Inflammation in Diabetic Wound Repair

项目摘要/摘要 糖尿病患者无法愈合的伤口是导致截肢的主要原因，并与 发病率和死亡率都很高。目前，对更有效的治疗方法的需求尚未得到满足，因为 现有的治疗方法使近70%的糖尿病伤口无法愈合。因此，迫切需要了解 创面愈合的病理生理学和寻找更有效的治疗策略 糖尿病伤口。 损伤后，单核细胞-巨噬细胞被招募到伤口，在那里它们从亲-巨噬细胞转变为 从炎症到抗炎的表型；组织修复所必需的一种基本开关。然而， 在糖尿病创面，巨噬细胞不能转变为抗炎、修复表型，从而导致 导致伤口愈合受损的全面促炎状态。尽管表观遗传机制 已被证明调节创面Mφ的表型，这些表观遗传通路在糖尿病中的调节 伤势仍不清楚。我们的初步数据发现，JMJD3，一种选择性地 使组蛋白3在27位赖氨酸(H3K27)去甲基化，增加炎症基因转录，并在 小鼠和人糖尿病伤口巨噬细胞。此外，我们发现JAK1-STAT3信号可能调节 考虑到这些发现，我们推测JMJD3在创伤M中的转录增加 信号转导诱导糖尿病创面M表达Jmjd3上调炎症基因表达此外， 我们推测，抑制糖尿病创面M中的JMJD3或JAK1，3可促进组织修复。这一假说将 通过以下具体目的进行研究：1)确定JAK1/STAT3介导的机制(S)， 调节Mφ特异性Jmjd3在正常和糖尿病伤口组织和人单核细胞中的表达。2)至 确定JAK1，3和JMJD3抑制对糖尿病创面Mφ极化和组织修复的影响。

PROJECT SUMMARY/ABSTRACT Non-healing wounds in diabetes are the leading cause of lower extremity amputations and are associated with significant morbidity and mortality. Currently, there is an unmet need for more effective therapies, since existing treatments leave nearly 70% of diabetic wounds unhealed. Thus, a critical need exists for understanding the pathophysiology of wound healing and identifying more effective treatment strategies for patients with diabetic wounds. Following injury, monocyte-macrophages are recruited to the wound where they transition from a pro- inflammatory to an anti-inflammatory phenotype; an essential switch that is necessary for tissue repair. However, in diabetic wounds, macrophages fail to transition to an anti-inflammatory, reparative phenotype, thereby leading to an overall pro-inflammatory state that results in impaired wound healing. Although epigenetic mechanisms have been shown to regulate Mφ phenotype in wounds, the regulation of these epigenetic pathways in diabetic wounds remains unknown. Our preliminary data identifies that JMJD3, a histone demethylase that selectively demethylates histone 3 at lysine 27 (H3K27), increases inflammatory gene transcription and is increased in murine and human diabetic wound macrophages. Further, we found that JAK1-STAT3 signaling may regulate Jmjd3 transcription in wound Ms. Considering these findings, we hypothesize that increased JAK1-STAT3 signaling induces Jmjd3 in diabetic wound Ms and upregulates inflammatory gene expression. Further, we postulate that inhibiting JMJD3 or JAK1,3 in diabetic wound Ms improves tissue repair. This hypothesis will be investigated through the following specific aims: 1) To identify the JAK1/STAT3-mediated mechanism(s) that regulate Mφ-specific Jmjd3 expression in normal and diabetic wound tissue and human monocytes. 2) To determine the effects of JAK1,3 and JMJD3 inhibition on diabetic wound Mφ polarization and tissue repair.