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

JAK/STAT 对糖尿病伤口修复中巨噬细胞介导的炎症的调节

基本信息

批准号：
10385935
负责人：
Kevin Dale Mangum
金额：
$ 7.5万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10385935
关键词：
Amputation Animals Anti-Inflammatory Agents Chromatin Chronic Data Development Diabetes Mellitus Diabetic mouse Enhancers Enzymes Epigenetic Process Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Healthcare Systems Histones Human Impaired wound healing Inflammation Inflammatory Injury JAK1 gene Kinetics Laboratories Lead Link Logic Lower Extremity Lysine Mediating Morbidity - disease rate Mus Myelogenous Non-Insulin-Dependent Diabetes Mellitus Normal tissue morphology Partner in relationship Pathway interactions Patients Pharmacology Phase Phenotype Post-Translational Protein Processing Process Regulation Research Design STAT3 gene Scientist Signal Transduction Site Techniques Testing United States base cost diabetic diabetic ulcer diabetic wound healing effective therapy epigenetic regulation experimental study healing histone demethylase improved macrophage monocyte mortality mouse model new therapeutic target non-healing wounds novel novel therapeutics promoter recruit repaired skills success therapeutic target tissue repair treatment strategy wound wound healing

项目摘要

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.

项目概要/摘要糖尿病患者的伤口不愈合是下肢截肢的主要原因，并且与目前，对更有效的治疗方法的需求尚未得到满足。现有的治疗方法使近 70% 的糖尿病伤口无法愈合，因此，迫切需要了解这一点。伤口愈合的病理生理学并为患者确定更有效的治疗策略糖尿病伤口。受伤后，单核细胞-巨噬细胞被募集到伤口，在那里它们从亲-巨噬细胞转变为炎症到抗炎表型；组织修复所必需的重要转变。在糖尿病伤口中，巨噬细胞无法转变为抗炎、修复表型，从而导致尽管有表观遗传机制，但总体上仍处于促炎状态，导致伤口愈合受损。已被证明可以调节伤口中的 Mφ 表型，糖尿病患者中这些表观遗传途径的调节我们的初步数据表明，JMJD3 是一种选择性的组蛋白去甲基化酶。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在此外，我们发现 JAK1-STAT3 信号传导可能调节小鼠和人类糖尿病伤口巨噬细胞。考虑到这些发现，我们认为 Ms 中的 Jmjd3 转录损伤增加了 JAK1-STAT3。信号传导在糖尿病伤口 Ms 中诱导 Jmjd3 并上调炎症基因表达。我们假设抑制糖尿病伤口 Ms 中的 JMJD3 或 JAK1,3 可以改善组织修复。通过以下具体目标进行研究： 1) 确定 JAK1/STAT3 介导的机制调节正常和糖尿病伤口组织和人单核细胞中 Mφ 特异性 Jmjd3 的表达 2) To。确定 JAK1,3 和 JMJD3 抑制对糖尿病伤口 Mφ 极化和组织修复的影响。