Mechanistic study of Small-molecular Therapy in diabetic Wound Healing

小分子治疗糖尿病伤口愈合的机制研究

• 批准号: 10569598
• 负责人: Jiemei Wang
• 金额: $ 37.47万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569598
• 关键词: ANGPT1 gene; Affect; Amputation; Angiogenic Factor; Animal Model; Animals; Cell Culture Techniques; Cell Survival; Cell physiology; Cells; Chronic; Clinic; Critical Pathways; Cytoprotection; Data; Dermal; Diabetes Mellitus; Diabetic Foot Ulcer; Drug Metabolic Detoxication; Endothelial Cells; Enzymes; FDA approved; Gene Expression; Glucose; Glycolysis; Goals; Health; Human; Impairment; In Vitro; Knowledge; Lactoylglutathione Lyase; Literature; Modeling; Molecular; Oral; Outcome; Overweight; Pathway interactions; Patients; Permeability; Play; Population; Proliferating; Proteins; Proteomics; Protocols documentation; Regimen; Regulation; Reporting; Research; Role; Signal Transduction; Stress; Testing; Therapeutic; Topical application; Treatment Protocols; Vascular Endothelial Cell; Wound models; angiogenesis; blood vessel development; burn wound; chronic wound; db/db mouse; diabetic; diabetic patient; diabetic ulcer; diabetic wound healing; dietary; efficacy evaluation; glycation; improved; in vivo; metabolic profile; migration; non-healing wounds; novel; obese person; small molecule; success; tissue repair; trans-resveratrol; translational potential; traumatic wound; wound; wound care; wound closure; wound healing; wound treatment

Diabetic foot ulcers that lead to amputations are a major health problem affecting ~20% of the 30 million diabetic patients in the US. The current regimen has limited success, and the amputation rates remain high. Therefore, understanding molecular mechanisms for compounds with translational potential is a crucial step toward making a breakthrough in wound care protocols. Endothelial cells (ECs) are indispensable cellular components for wound angiogenesis. However, EC functions are impaired in patients with diabetes. The coformulation of two dietary compounds - Trans-resveratrol (tRES) and hesperetin (HESP) - improves glucose metabolic profile and arterial function in overweight and obese subjects through inducing the gene expression of glyoxalase 1 (GLO1), an enzyme that detoxifies reactive metabolites during glycolysis and protects cells against glycation stress. Our pilot data indicated that tRES+HESP improved wound healing in diabetic animals with an increase in GLO1 expression. However, its effects are likely far beyond inducing GLO1 expression because tRES+HESP treated ECs produced many pro-angiogenic factors, including angiopoietin-1 (ANGPT1) that plays an essential role in angiogenesis. Therefore, it is critical to determine proteins that are regulated by tRES+HESP in angiogenesis and tissue repair. The objective of this project is to fill the knowledge gap of the role of tRES+HESP in rescuing the disrupted angiogenesis in diabetes, and our long-term goal is to develop therapeutic strategies for diabetic wound repair. We hypothesize that tRES+HESP augments angiogenesis and improves diabetic wound healing through enhancing the expression of GLO1 and a potent pro-angiogenic factor, ANGPT1, and through novel changes in additional proteins in pathways critical to diabetic wound repair. Aim 1: Identification of molecular pathways and protein changes induced by tRES+HESP in human dermal microvascular ECs in vitro. Sub-aim 1: Determine to what extent tRES+HESP can rescue diabetic endothelial cell function in vitro. Sub-aim 2: Determine how vital ANGPT1 is in tRES+HESP-induced angiogenesis in vitro. Sub-aim 3: Discover new proteins and pathways responsible for the benefit of tRES+HESP treatment in endothelial cell function in vitro using state- of-the-art proteomics. Aim 2: Determine the therapeutic potential of tRES+HESP and its underlying molecular mechanisms in chronic diabetic wounds in vivo. Sub-aim 1: Determine the efficacy of tRES+HESP on wound healing in a newly developed diabetic chronic wound model in db/db mice. Sub-aim 2: Determine the role of ANGPT1 in the tRES+HESP-induced improvement in wound healing in vivo. Sub-aim 3: Discover new proteins and pathways responsible for the benefit of tRES+HESP treatment in diabetic wound repair in vivo using state- of-the-art proteomics. The outcome of the proposed research will determine the efficacy of topical application of this formula, tRES+HESP, in diabetic wound healing, and will unveil underlying molecular mechanisms for its beneficial effect. Since tRES+HESP has not been approved by the FDA to treat diabetic wound healing yet, these results may facilitate the FDA approval of this coformulation in diabetic wound treatment.

导致截肢的糖尿病足溃疡是影响3000万糖尿病的约20％的主要健康问题 美国的患者。当前的方案的成功有限，截肢率仍然很高。所以， 了解具有转化势的化合物的分子机制是使其迈向的至关重要的步骤 伤口护理方案的突破。内皮细胞（EC）是必不可少的细胞成分 伤口血管生成。但是，糖尿病患者的EC功能受损。两者的合成 饮食化合物 - 反式白垩酚（TRE）和硫代素（HESP） - 改善葡萄糖代谢谱和 通过诱导糖酶1（GLO1）的基因表达，超重和肥胖受试者中的动脉功能 在糖酵解过程中对活性代谢产物排毒并保护细胞免受糖基化胁迫的酶。我们的 试验数据表明，TRE+HESP改善了糖尿病动物的伤口愈合，GLO1增加 表达。但是，由于TRE+HESP处理 ECS产生了许多促血管生成因素，包括血管生成素-1（Angpt1），在 血管生成。因此，确定由Tres+HESP在血管生成中调节的蛋白质至关重要 和组织修复。该项目的目的是填补TRE+HESP在救援中的作用的知识差距 糖尿病中的血管生成干扰，我们的长期目标是制定糖尿病治疗策略 伤口修复。我们假设TRE+HESP增强血管生成并改善糖尿病伤口愈合 通过增强GLO1的表达和有效的促血管生成因子Angpt1，并通过新颖 对糖尿病伤口修复至关重要的途径中其他蛋白质的变化。目标1：识别分子 在体外人类皮肤微血管EC中，TRE+HESP诱导的途径和蛋白质变化。子 1：确定TRE+HESP在多大程度上可以在体外营救糖尿病内皮细胞功能。 Sub-aim 2： 确定在TRE+HESP诱导的体外血管生成中的重要Angpt1。 Sub-aim 3：发现新蛋白质 以及负责TRE+HESP处理在体外使用状态 - 蛋白质组学。 AIM 2：确定TRE+HESP及其基础分子的治疗潜力 体内慢性糖尿病伤口的机制。子-IAM 1：确定TRE+HESP对伤口的功效 在新发展的DB/DB小鼠中糖尿病性慢性伤口模型中的愈合。 Sub-aim 2：确定 TRE+HESP诱导的体内伤口愈合的改善。 Sub-aim 3：发现新蛋白质 以及负责TRE+HESP治疗在体内使用状态 - 蛋白质组学。拟议研究的结果将确定局部应用的功效 在糖尿病伤口愈合中，该公式的TRE+HESP，并将推出其基本的分子机制 有益的效果。由于TRE+HESP尚未获得FDA的批准来治疗糖尿病伤口愈合，因此 这些结果可能有助于FDA在糖尿病伤口治疗中获得这种合成的批准。