NRF2 Activation in Diabetic Wound Healing

NRF2 激活在糖尿病伤口愈合中的作用

• 批准号: 10386811
• 负责人: May Barakat
• 金额: $ 5.18万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-16 至 2026-04-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10386811
• 关键词: Amputation; Antioxidants; Automobile Driving; Basement membrane; Binding; Biological Assay; Biological Models; Blood Vessels; Cells; Chronic; Collagen; Complication; Data; Defect; Development; Diabetes Mellitus; Diabetic Neuropathies; Diabetic mouse; Economic Burden; Equilibrium; Exhibits; Gene Expression; Genes; Genomics; Goals; Histologic; Human; Hydrogen Peroxide; Impaired healing; Impaired wound healing; Impairment; In Vitro; Inflammation; Investigation; Lead; Leg Ulcer; Life; Lipid Peroxides; Lower Extremity; Measures; Medical; Methods; Morbidity - disease rate; Mus; Neuropathy; Outcome; Oxidative Stress; Pathology; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Prevention; Process; Research; Role; Savings; Skin; Solubility; Specificity; Superoxide Dismutase; Testing; Time; Tissues; Topical application; Vascular Diseases; Work; Wound healing therapy; activating transcription factor; angiogenesis; catalase; chronic ulcer; chronic wound; db/db mouse; diabetes management; diabetic; diabetic patient; diabetic ulcer; diabetic wound healing; experimental study; healing; improved; in vivo; in vivo Model; innovation; insight; macrophage; mortality; non-diabetic; non-healing wounds; novel; nuclear factor-erythroid 2; response; restoration; small molecule; social; tool; transcription factor; transcriptome; transcriptome sequencing; treatment effect; wound; wound closure; wound healing; wound treatment

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.

项目摘要/摘要 对于糖尿病患者来说，慢性伤口的发展是一种危及生命的并发症。 仅在美国，每年就有超过10万人需要截肢。尽管有了改进 在糖尿病的治疗中，由于糖尿病创面固有的缺陷，糖尿病创面的治疗仍然具有挑战性 糖尿病患者与正常皮肤的伤口愈合。潜在的血管疾病，神经疾病，炎症增加， 糖尿病导致的基底膜增厚使皮肤容易出现无法愈合的伤口。 此外，糖尿病皮肤表现出氧化应激增加和核因子红系表达减少。 2相关因子2(NRF2)，一种转录因子，激活保护细胞免受 氧化应激。一些研究表明，NRF2的激活可能是管理层的相关目标 和预防慢性糖尿病伤口。目前的方案利用了新的小分子NRF2激活剂 与现有化合物相比，它们表现出更高的结合特异性和更低的致突变性， 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NRF2激活对糖尿病皮肤的影响。这项工作的长期目标是发展 局部应用NRF2激活药物治疗人类慢性糖尿病创面。 目前研究的目标是测试高度特异和新颖的NRF2的能力 促进糖尿病创面愈合并了解其作用机制的激活剂。在……里面 本研究将在db/db小鼠身上研究NRF2激活对糖尿病创面愈合的影响。 描述了糖尿病的活体模型系统。目标1A将确定这种新型NRF2的效果 促进伤口愈合的激活剂，包括伤口闭合、氧化应激和组织修复的质量。 目的1B将利用全组织RNA测序和功能通路分析来研究 糖尿病创面中转录水平的NRF2激活。数据将被用来确定 NRF2调控的功能通路在糖尿病皮肤病理中起重要作用。Aim 2将研究 我们的候选分子对巨噬细胞的影响，并研究这些新的NRF2激活剂是否通过 改善糖尿病创面愈合中的巨噬细胞功能。核转录因子NRF2激活对大鼠血管内皮细胞生长的影响 糖尿病伤口愈合可能导致开发出一种拯救生命、有效和实用的患者药物 患有慢性糖尿病的伤口。