The Interferon-beta (IFN-beta)/SETDB2 Epigenetic Axis Regulates Inflammation And Metabolism In Diabetic Wounds

项目总结/摘要 2型糖尿病（T2 D）患者的不愈合伤口是发病率和死亡率的主要原因， 正以惊人的速度增长控制巨噬细胞功能的因素以及这些细胞如何转变 创伤组织中从炎性表型到修复表型的变化尚不清楚; 我们预防和治疗这些创伤的能力。我们的实验室正在研究新的表观遗传变化，诱导 通过组蛋白的后过渡修饰，作为在细胞周期中调节巨噬细胞表型的机制。 伤口愈合我们目前的数据表明，在创伤后建立的细胞因子环境诱导 巨噬细胞中控制基因转录的特定表观遗传机制的表达，因此， 功能使用人类细胞和我们的实验性小鼠伤口愈合模型，我们已经确定， 干扰素β（IFNβ）诱导SETDB 2的表达，SETDB 2是一种基于表观遗传的赖氨酸甲基转移酶， 负责设置一个抑制性组蛋白标记，导致炎症和代谢的沉默， 基因.这一系列的事件有利于正常的伤口愈合，允许从创伤性愈合转变为创伤性愈合。 炎症转化为促进愈合所需的修复性巨噬细胞表型。我们假设， 正常伤口愈合的演变，IFNβ介导的伤口巨噬细胞中SETDB 2的诱导 抑制NF κ B介导的炎症和代谢基因，从而减少伤口 炎症和增强的伤口修复。我们进一步假设，这一过程不会发生在 糖尿病伤口，其中SETDB 2在伤口巨噬细胞中未被诱导，导致增加的 炎症和不愈合的伤口。将通过以下具体目标对这一假设进行研究： 1)阐明SETDB 2对正常和糖尿病伤口中NFkB介导的基因表达的调节 巨噬细胞; 2）确定IFNβ介导的上调巨噬细胞特异性SETDB 2的机制 在正常和糖尿病伤口组织中的表达;和3）建立SETDB 2调节的尿酸对糖尿病伤口组织中的表达的作用。 正常和糖尿病伤口巨噬细胞表型。

PROJECT SUMMARY/ABSTRACT Non-healing wounds in patients with Type 2 Diabetes (T2D) are a major cause of morbidity and mortality and are increasing at an alarming rate. The factors controlling macrophage function and how these cells transition from an inflammatory to a reparative phenotype in wound tissues are not understood; leaving a large deficit in our ability to prevent and treat these wounds. Our laboratory is investigating novel epigenetic changes, induced via post-transitional modifications of histones, as mechanism(s) to regulate the macrophage phenotype during wound healing. We present data that the cytokine environment established in wounds following injury induces the expression of specific epigenetic machinery in macrophages that control gene transcription, and hence, function. Using human cells and our experimental murine model of wound healing, we have identified that interferon-beta (IFNβ) induces the expression of SETDB2, an epigenetic-based lysine methyltransferase that is responsible for setting a suppressive histone mark that results in the silencing of inflammatory and metabolic genes. This sequence of events is beneficial in normal wound healing, allowing for the transition from an inflammatory to a reparative macrophage phenotype needed to promote healing. We hypothesize that during the evolution of normal wound healing, IFNβ-mediated induction of SETDB2 in wound macrophages represses NFKB-mediated inflammatory and metabolic genes resulting in decreased wound inflammation and enhanced wound repair. We further postulate that this process does not occur in diabetic wounds where SETDB2 is not induced in wound macrophages, resulting in increased inflammation and non-healing wounds. This hypothesis will be investigated via the following specific aims: 1) Elucidate the regulation of NFkB-mediated gene expression by SETDB2 in normal and diabetic wound macrophages; 2) Determine the IFNβ-mediated mechanism(s) that upregulate macrophage-specific SETDB2 expression in normal and diabetic wound tissue; and 3) Establish the role of SETDB2-regulated uric acid on normal and diabetic wound macrophage phenotypes during healing.