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

描述（由申请人提供）：慢性不愈合伤口作为美国医疗保健持续存在。伴有高脂血症和高血糖的II型糖尿病在超重的美国人中很常见，是神经血管并发症的主要危险因素。糖尿病控制和并发症试验的多项分析表明，尽管随后进行了强化胰岛素干预，但接受标准胰岛素治疗的患者仍表现出持续的炎症反应并发生血管并发症。这些发现产生了被广泛接受的“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的相关性日益增加，这种关联对于理解慢性糖尿病伤口的病理生理学至关重要。我们对这个新项目的假设是：1）葡萄糖和脂肪酸水平升高，即使是短暂的，也会以持续的方式改变真皮微血管内皮细胞和神经祖细胞之间的旁分泌相互作用; 2）抗氧化剂消除了对葡萄糖和脂肪酸的功能失调反应。我们将通过解决以下三个具体目标来测试我们的假设：1。以确定短暂暴露于升高的葡萄糖和脂肪酸水平是否会引起代谢记忆，从而诱导微血管内皮细胞和神经祖细胞对损伤的反应发生持续变化。我们确定是否真皮微血管内皮细胞和神经前体细胞有受损的反应后，短暂暴露于葡萄糖和脂肪酸的损伤。基于已发表的其他细胞类型的数据，我们预计短暂的葡萄糖和脂肪酸暴露对这些细胞具有持续的表观遗传效应。2.确定抗氧化剂是否消除升高的葡萄糖和脂肪酸对微血管内皮细胞和神经祖细胞的影响。我们建议评估抗氧化剂维生素E和C是否逆转葡萄糖和脂肪酸对内皮细胞和神经祖细胞反应的影响，这将确定葡萄糖和脂肪酸的有害影响是否可逆或可预防。3.确定短暂的高脂肪、高糖饮食是否影响糖尿病和非糖尿病小鼠的伤口愈合。我们相信，在饮食中补充抗氧化剂维生素E和C将消除不良的饮食影响，并防止表观遗传效应。

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.