NEUROENDOCRINE REGULATION OF WOUND HEALING DURING AGING

有效的皮肤伤口愈合迅速恢复保护屏障的受伤表面。然而，延迟愈合可以发生的任何数量的过程，影响伤口愈合的早期炎症阶段的结果。例如，与衰老相关的生理变化和心理压力的免疫抑制影响已被证明会减缓伤口愈合。促炎细胞因子、趋化因子和生长因子的反应对于多形核白细胞、单核细胞和角化细胞在伤口部位的协调功能是必要的。因此，快速表达编码免疫调节蛋白和肽的基因对于有效愈合是必要的。再加上年龄相关的免疫衰老，压力使老年人在手术或意外伤口后感染的风险很高。随着年龄的增长和压力的增加，血液中的皮质醇/脱氢表雄酮比例增加，这可能是与两种状态相关的分解代谢作用的原因。据报道，脱氢表雄酮（及其代谢物AED）具有免疫恢复、抗衰老和抗糖皮质激素的特性。因此，在这些研究中，我们将研究AED如何平衡皮肤伤口愈合过程中年龄和压力介导的炎症/免疫反应的减少。将使用已建立的小鼠模型来检查早期阶段基因表达的动力学和模式。进一步的研究将寻求确定调节促炎细胞因子、趋化因子和生长因子基因表达的压力和年龄相关变量。该应用程序的具体目的是：(a)确定应激和衰老对伤口愈合早期促炎细胞因子、趋化因子和生长因子基因表达模式和动力学的影响；(b)检查创伤愈合过程中影响基因表达的应激诱导的神经内分泌反应；(3)确定雄烯二醇（脱氢表雄酮的代谢物）在应激和年龄相关的伤口愈合减缓中的治疗效果。

Efficient cutaneous wound healing quickly restores the protective barrier to an injured surface. However, delayed healing can occur as a consequence of any number of processes that affect the early inflammatory stages of wound healing. For example, the physiological changes associated with aging and the immunosuppressive influences of psychological stress have been shown to slow wound healing. Pro- inflammatory cytokine, chemokine and growth factor responses are necessary for the coordinated function of polymorphonuclear leukocytes, monocytes and keratinocytes at the wound site. Therefore, the rapid expression of genes encoding immunomodulatory proteins and peptides is necessary for efficient healing. Combined with age-related immunosenescence, stress puts elderly individuals at high risk for infection after surgical or accidental wounds. With advancing age and during times of stress there is an increase in the cortisol/DHEA ration in the blood which may be responsible for catabolic effects associated with both states. DHEA (and its metabolite, AED) have been reported to have immunorestorative, anti-aging and anti-glucocorticoid properties. Therefore, in these studies we will investigate how AED counter balances age- and stress-mediated decrements in inflammatory/immune responses during cutaneous wound healing. An established murine model will be used to examine the kinetics and patterns of gene expression during the early phases. Further studies will seek to identify stress and age associated variables that modulate the expression of pro-inflammatory cytokine, chemokine and growth factor genes. The specific aims of this application are: (a) Determine the influence of stress and aging on the pattern and kinetics of pro-inflammatory cytokine, chemokine, and growth factor gene expression during the early stages of wound healing; (b) Examine the stress-induced neuroendocrine responses that impact gene expression during wound healing; (3) Determine the therapeutic efficacy of androstenediol (a metabolite of DHEA) treatment in the context stress- and age-associated slowing of wound healing.