NEUROENDOCRINE REGULATION OF WOUND HEALING DURING AGING

衰老过程中伤口愈合的神经内分泌调节

• 批准号: 6642240
• 负责人: John F Sheridan
• 金额: $ 13.78万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6642240
• 关键词: aging; androgens; behavioral /social science research tag; chemokine; cytokine; dehydroepiandrosterone; gene expression; genetic regulation; glucocorticoids; growth factor; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; immune system; immunocytochemistry; immunoregulation; immunosuppression; in situ hybridization; inflammation; laboratory mouse; leukocyte activation /transformation; macrophage; neuroendocrine system; neutrophil; psychological stressor; wound healing

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.

有效的皮肤伤口愈合快速恢复受伤表面的保护屏障。然而，延迟愈合可作为影响伤口愈合的早期炎症阶段的任何数量的过程的结果而发生。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反应对于伤口部位多形核白细胞、单核细胞和角质形成细胞的协调功能是必要的。因此，编码免疫调节蛋白和肽的基因的快速表达对于有效愈合是必要的。与年龄相关的免疫衰老相结合，压力使老年人在手术或意外伤口后感染的风险很高。随着年龄的增长和在压力的时候，血液中的皮质醇/DHEA比例增加，这可能是与这两种状态相关的分解代谢作用的原因。DHEA（及其代谢产物，AED）已被报道具有免疫恢复，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。建立的鼠模型将用于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压力和年龄相关的变量，调节促炎细胞因子，趋化因子和生长因子基因的表达。本申请的具体目的是：（a）确定应激和老化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的模式和动力学的影响;（B）检查影响伤口愈合期间基因表达的应激诱导的神经内分泌应答;（3）确定雄烯二醇（DHEA的代谢物）治疗在应激和年龄相关的伤口愈合减缓的背景下的治疗功效。