NRF2 Activation in Diabetic Wound Healing

项目总结/摘要 对于糖尿病（DM）患者，慢性伤口的发展是威胁生命的并发症 仅在美国每年就有超过10万例下肢截肢手术。尽管有所改善 在糖尿病的管理中，糖尿病伤口的治疗仍然具有挑战性，这是由于 糖尿病患者与正常皮肤的伤口愈合。基础血管病变、神经病变、炎症增加， 以及由于糖尿病而增厚的基底膜使皮肤易于形成不愈合的伤口。 此外，糖尿病皮肤表现出增加的氧化应激和减少的核因子红细胞表达 2-相关因子2（NRF 2），一种激活保护细胞免受增加的细胞凋亡的途径的转录因子。 氧化应激几项研究表明，NRF 2激活可能是一个相关的目标，为管理 和预防慢性糖尿病伤口。目前的建议利用新的小分子NRF 2激活剂 其相对于现有化合物表现出增加的结合特异性和降低的致突变性， 而不牺牲溶解度、效力或稳定性。这些新型分子是一种创新和最佳的工具， 研究NRF 2激活对糖尿病皮肤的影响。这项工作的长期目标是发展 用于治疗人慢性糖尿病伤口的局部施用的NRF 2活化药物。 目前研究的目的是测试高度特异性和新颖的NRF 2 活化剂，以改善糖尿病伤口愈合，并了解其作用机制。在 本研究将在db/db小鼠中研究NRF 2活化对糖尿病伤口愈合的影响， 在DM的体内模型系统中表征。目的1A将确定这种新型NRF 2的作用 在伤口愈合，包括伤口闭合，氧化应激和组织恢复的质量的活化剂。 目的1B将采用全组织RNA测序和功能途径分析来研究 转录组水平上糖尿病伤口中的NRF 2活化。这些数据将用于确定 由NRF 2调节的功能途径对糖尿病皮肤病理学是重要的。目标2将审查 我们的候选分子对巨噬细胞的影响，并研究这些新的NRF 2激活剂是否通过 改善糖尿病伤口愈合中的巨噬细胞功能。研究NRF 2激活对人乳腺癌细胞的影响。 糖尿病伤口愈合可能会导致开发一种挽救生命的，有效的，实用的药物， 慢性糖尿病伤口

PROJECT SUMMARY / ABSTRACT For patients with diabetes mellitus (DM), the development of chronic wounds is a life-threatening complication that necessitates over 100,000 lower extremity amputations per year in the U.S. alone. Despite improvements in the management of DM, the treatment of diabetic wounds remains challenging due to the inherent defects in wound healing in diabetic vs. normal skin. Underlying vasculopathies, neuropathies, increased inflammation, and thickened basement membranes due to diabetes predispose the skin to developing non-healing wounds. Moreover, diabetic skin exhibits increased oxidative stress and decreased expression of nuclear factor erythroid 2–related factor 2 (NRF2), a transcription factor that activates a pathway that protects cells from increased oxidative stress. Several studies suggest that NRF2 activation could be a relevant target for the management and prevention of chronic diabetic wounds. The current proposal utilizes novel small molecule NRF2 activators that exhibit increased specificity of binding and decreased mutagenicity relative to existing compounds, without sacrificing solubility, potency, or stability. These novel molecules are an innovative and optimal tool to study the effects of NRF2 activation on diabetic skin. The long-term objective of this work is to develop topically-applied NRF2-activating drugs for the treatment of human chronic diabetic wounds. The goals of the current research are to test the ability of highly specific and novel NRF2 activators to improve diabetic wound healing and to understand their mechanisms of action. In this study, the effects of NRF2 activation on diabetic wound healing will be investigated in db/db mice, a well- characterized in vivo model system of DM. Aim 1A will determine the effects of this novel class of NRF2 activators on wound healing, including wound closure, oxidative stress, and the quality of tissue restoration. Aim 1B will employ whole-tissue RNA-sequencing and functional pathway analysis to investigate the effects of NRF2 activation in diabetic wounds at the transcriptome level. The data will be used to determine which functional pathways regulated by NRF2 are important to diabetic skin pathology. Aim 2 will examine the effects of our candidate molecules on macrophages and investigate whether these novel NRF2 activators act by improving macrophage function in diabetic wound healing. Investigation into the effects of NRF2 activation on diabetic wound healing may lead to the development of a life-saving, effective, and practical drug for patients with chronic diabetic wounds.