Surgical wound repair: effect of metabolic memory on neuro-endothelial responses

手术伤口修复：代谢记忆对神经内皮反应的影响

• 批准号: 8489307
• 负责人: NICOLE SIMONE GIBRAN
• 金额: $ 28.33万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8489307
• 关键词: Address; Affect; American; Antioxidants; Apoptosis; Arthritis; Ascorbic Acid; Blood Glucose; Blood Vessels; Cardiovascular system; Cells; Characteristics; Chronic; Coculture Techniques; Complications of Diabetes Mellitus; Cutaneous; DNA; DNA Methylation; Data; Dermal; Development; Diabetes Mellitus; Diabetic mouse; Diabetic wound; Diet; Endothelial Cells; Epidemiology; Epigenetic Process; Etiology; Exhibits; Exposure to; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Gene Expression; Genes; Glucose; Goals; Healthcare; Heart Diseases; Histones; Hyperglycemia; Hyperlipidemia; Impaired wound healing; Impairment; Inflammatory; Inflammatory Response; Injury; Insulin; Intervention; Malignant Neoplasms; Measures; Memory; Metabolic; Methylation; Modification; Mus; Nerve; Nerve Degeneration; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Oxidative Stress; Paracrine Communication; Pathway interactions; Patients; Publishing; Reporting; Retinal Diseases; Risk Factors; Role; Skin; Stem cells; Surgical wound; System; Testing; Tocopherols; Ulcer; Vitamin E; Work; Wound Healing; angiogenesis; base; cell type; diabetes control; diabetic; dietary supplements; histone modification; human disease; injury and repair; migration; nerve stem cell; neuroinflammation; non-diabetic; novel; novel strategies; paracrine; prevent; response; response to injury; theories

DESCRIPTION (provided by applicant): Chronic non-healing wounds persist as a US health care. Type II diabetes mellitus with characteristic hyperlipidemia and hyperglycemia is common in overweight Americans and is a major risk factor for neurovascular complications. Multiple analyses from the Diabetes Control and Complications Trial demonstrate that patients treated with standard insulin therapy exhibit sustained inflammatory responses and develop vascular complications in spite of subsequent intensive insulin intervention. These findings have generated the widely accepted 'metabolic memory' theory that transient hyperglycemia involves epigenetic modifications that alter gene expression. Epigenetic modifications have been increasingly correlated with human diseases and such associations are essential for understanding the pathophysiology of chronic diabetic wounds. Our hypothesis for this new project is that 1) elevated levels of glucose and fatty acids, even transiently, alter paracrine interactions between dermal microvascular endothelial cells and neural progenitor cells in a sustained manner and 2) anti-oxidants abrogate the dysfunctional responses to glucose and fatty acids. We will test our hypothesis by addressing the following three Specific Aims: 1. to determine whether transient exposure to elevated glucose and fatty acid levels causes a metabolic memory that induces sustained changes in microvascular endothelial and neural progenitor cell responses to injury. We determine whether dermal microvascular endothelial cells and neural progenitor cells have impaired responses to injury after transient exposure to glucose and fatty acids. Based on published data on other cell types, we expect that transient glucose and fatty acid exposure has sustained epigenetic effects on these cells. 2. To determine whether antioxidants abrogate the effects of elevated glucose and fatty acids on microvascular endothelial cells and nerve progenitor cells. Our proposal to evaluate whether antioxidants vitamins E and C reverse effects of glucose and fatty acids on endothelial cell and neural progenitor cell responses will determine whether detrimental effects of glucose and fatty acids are reversible or preventable. 3. To determine whether a transient high fat, high glucose diet affects wound healing in diabetic and non-diabetic mice. We believe that supplementing the diet with the antioxidants vitamins E and C will abrogate the adverse dietary effects and will prevent epigenetic effects.

描述（由申请人提供）：慢性非治疗伤口仍然是美国医疗保健。具有特征性高脂血症和高血糖的II型糖尿病在超重美国人中很常见，是神经血管并发症的主要危险因素。来自糖尿病控制和并发症试验的多次分析表明，接受标准胰岛素治疗治疗的患者表现出持续的炎症反应，尽管随后进行了强化胰岛素干预，但仍会出现血管并发症。这些发现产生了广泛接受的“代谢记忆”理论，即短暂性高血糖涉及改变基因表达的表观遗传修饰。表观遗传修饰与人类疾病越来越多，这种关联对于理解慢性糖尿病伤的病理生理至关重要。我们对这个新项目的假设是：1）葡萄糖和脂肪酸的水平升高，甚至瞬时会改变皮肤微血管内皮细胞和神经祖细胞之间的旁分泌相互作用，并以持续的方式和2）抗氧化剂消除了功能障碍的反应对葡萄糖和脂肪酸的功能障碍反应。我们将通过解决以下三个特定目的来检验假设：1。确定瞬时暴露于葡萄糖和脂肪酸水平是否会导致代谢记忆，从而引起微血管内皮和神经祖细胞对损伤的持续变化。我们确定皮肤微血管内皮细胞和神经祖细胞是否在短暂暴露于葡萄糖和脂肪酸后对损伤的反应受损。基于有关其他细胞类型的公开数据，我们期望瞬时葡萄糖和脂肪酸暴露对这些细胞具有持续的表观遗传作用。 2。确定抗氧化剂是否消除了葡萄糖和脂肪酸对微血管内皮细胞和神经祖细胞细胞的影响。我们评估葡萄糖和脂肪酸对内皮细胞和神经祖细胞反应的抗氧化剂E和C反向作用的建议是否会确定葡萄糖和脂肪酸的有害作用是可逆的还是可预防的。 3。为了确定瞬时高脂，高葡萄糖饮食是否会影响糖尿病和非糖尿病小鼠的伤口愈合。我们认为，用抗氧化剂维生素E和C补充饮食会消除不良饮食的影响，并防止表观遗传作用。