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

项目概要/摘要 糖尿病伤口不愈合是下肢截肢的主要原因， 具有显著的发病率和死亡率。目前，对于更有效的疗法存在未满足的需求，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 伤口愈合的病理生理学，并确定更有效的治疗策略， 糖尿病伤口 在损伤后，单核细胞-巨噬细胞被募集到伤口，在那里它们从亲-巨噬细胞转变为亲-巨噬细胞。 炎症表型转化为抗炎表型;是组织修复所必需的基本开关。然而，在这方面， 在糖尿病伤口中，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整体促炎状态。虽然表观遗传机制 已经显示出调节伤口中的M φ表型，糖尿病患者中这些表观遗传途径的调节， 伤口仍然未知。我们的初步数据表明，JMJD 3是一种选择性地 使组蛋白3在赖氨酸27（H3K27）处去甲基化，增加炎症基因转录，并增加 鼠和人糖尿病伤口巨噬细胞。此外，我们发现JAK1-STAT3信号通路可以调节 创伤性骨髓瘤中的Jmjd3转录。考虑到这些发现，我们假设增加JAK1-STAT3 信号传导诱导糖尿病伤口MLS中的Jmjd3并上调炎性基因表达。此外，本发明还 我们推测，抑制糖尿病伤口MLS中的JMJD 3或JAK 1，3可改善组织修复。这一假设将 通过以下具体目的进行研究：1）鉴定JAK1/STAT3介导的机制， 在正常和糖尿病伤口组织和人单核细胞中调节M φ特异性Jmjd3表达。2)到 确定JAK 1、3和JMJD 3抑制对糖尿病伤口M φ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.