Targeted therapy to reverse TLR4/DLL4 dysregulation in diabetic wounds

项目摘要/摘要 2型糖尿病(T2D)患者的不可愈合伤口是发病率和死亡率的主要原因，并且 以惊人的速度增长。T2D患者伤口愈合失败是最常见的原因 截肢在美国，5年死亡率接近50%。因此，迫切需要理解 T2D的伤口愈合缺陷，以开发有针对性的治疗方法。公布的数据来自我们的实验室和我的新 初步数据表明，糖尿病创面巨噬细胞中的TLR4信号上调了Notch配体， DLL4，并促进急性伤口的炎症。此外，在糖尿病创面巨噬细胞中，TLR4/DLL4 途径上调继发于表观遗传机制，由此增加MLL1，一种组蛋白 TLR4启动子上的甲基转移酶促进TLR4信号的增加。这增加了TLR4信令(通过 MyD88)上调糖尿病伤口中DLL4的表达MφS，并推动糖尿病的炎症和病理愈合。 我们建议的研究将建立TLR4是通过MLL1介导的机制在表观遗传上上调的 糖尿病创面巨噬细胞并直接调节DLL4的表达。这些结果导致了我们的假设 糖尿病创面巨噬细胞TLR4信号的增加增加了DLL4，从而促进了慢性 糖尿病创面的炎症和无法愈合。我们的数据表明，糖尿病的伤口修复可能会得到改善 通过局部靶向治疗TLR4抑制剂(S)和/或MLL1抑制剂(S)。为了检验我们的假设，我们将 追求以下目标：目标1：研究糖尿病创面中依赖TLR4的DLL4的调节 急、慢性糖尿病小鼠创伤模型中的巨噬细胞。目标2：确定本地是否 治疗性阻断TLR4或MLL1促进急、慢性糖尿病小鼠创面修复 受伤的模特。

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. Failure of wound healing in T2D patients represents the most common cause of amputation in the US with a 5-year mortality rate of nearly 50%. Thus, a critical need exists for understanding the wound healing defects in T2D in order to develop targeted therapies. Published data from our lab and my new preliminary data has identified that TLR4 signaling in diabetic wound macrophages upregulates the Notch ligand, DLL4, and promotes inflammation in acute wounds. Further, in diabetic wound macrophages, the TLR4/DLL4 pathway is upregulated secondary to an epigenetic mechanism whereby increased MLL1, a histone methyltransferase, on the Tlr4 promoter promotes increased TLR4 signaling. This increased TLR4 signaling (via MyD88) upregulates DLL4 in diabetic wound Mφs and drives inflammation and pathologic healing in diabetes. Our proposed studies will establish that TLR4 is epigenetically upregulated via an MLL1-mediated mechanism in diabetic wound macrophages and directly regulates DLL4 expression. These results have led to our hypothesis that increased TLR4 signaling in diabetic wound macrophages increases DLL4 which promotes chronic inflammation and non-healing in diabetic wounds. Our data suggest that diabetic wound repair may be improved via locally-targeted treatment with TLR4 inhibitor(s) and/or MLL1 inhibitor(s). To test our hypotheses, we will pursue the following Aims: Aim 1: To examine the TLR4-dependent regulation of DLL4 in diabetic wound macrophages in acute and chronic diabetic murine wound models. Aim 2: To determine if local therapeutic blockade of TLR4 or MLL1 improves diabetic wound repair in acute and chronic murine wound models.