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.

糖尿病足溃疡是导致截肢的主要健康问题，影响着3000万糖尿病患者中约20%的人