NRF2 Activation in Diabetic Wound Healing

NRF2 激活在糖尿病伤口愈合中的作用

• 批准号: 10612737
• 负责人: May Barakat
• 金额: $ 5.27万
• 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/10612737
• 关键词: Amputation; Antioxidants; Automobile Driving; Basement membrane; Binding; Biological Assay; Biological Models; Blood Vessels; Chronic; Collagen; Complication; Cytoprotection; Data; Defect; Development; Diabetes Mellitus; Diabetic Neuropathies; Diabetic mouse; Economic Burden; Epithelium; 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; Macrophage; 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; Skin; Solubility; Specificity; Superoxide Dismutase; Testing; Time; Tissues; Topical application; Vascular Diseases; Work; Wound healing therapy; 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; mortality; non-diabetic; non-healing wounds; novel; nuclear factor-erythroid 2; protective pathway; response; restoration; small molecule; social; tool; transcription factor; transcriptome; transcriptome sequencing; treatment effect; wound; wound care; 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.

项目概要/摘要 对于糖尿病 (DM) 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 100,000 例下肢截肢手术。尽管有所改进 在糖尿病的治疗中，由于糖尿病伤口的固有缺陷，糖尿病伤口的治疗仍然具有挑战性。 糖尿病与正常皮肤的伤口愈合。潜在的血管病变、神经病变、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细胞表达减少 2-相关因子 2 (NRF2)，一种转录因子，可激活保护细胞免受增加的影响的途径 氧化应激。多项研究表明 NRF2 激活可能是治疗的相关目标 和预防慢性糖尿病伤口。目前的提案利用新型小分子 NRF2 激活剂 相对于现有化合物，表现出更高的结合特异性和更低的致突变性， 不牺牲溶解度、效力或稳定性。这些新颖的分子是一种创新的最佳工具 研究 NRF2 激活对糖尿病皮肤的影响。这项工作的长期目标是开发 局部应用的 NRF2 激活药物用于治疗人类慢性糖尿病伤口。 当前研究的目标是测试高度特异性和新颖的NRF2的能力 激活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（一种良好的糖尿病伤口愈合模型）中研究 NRF2 激活对糖尿病伤口愈合的影响。 DM 体内模型系统的特征。目标 1A 将确定此类新型 NRF2 的效果 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。 目标 1B 将采用全组织 RNA 测序和功能途径分析来研究 糖尿病伤口中 NRF2 在转录组水平上的激活。该数据将用于确定哪些 NRF2 调节的功能通路对于糖尿病皮肤病理学很重要。目标 2 将检查 我们的候选分子对巨噬细胞的影响，并研究这些新型 NRF2 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 NRF2 激活对 糖尿病伤口愈合可能会导致开发出一种拯救患者生命、有效且实用的药物 患有慢性糖尿病伤口。