Behavioral/neuroendocrine regulation of wound healing

描述(摘自研究人员摘要)：这项建议的假设是，与应激相关的生理变化，下调促炎细胞因子、趋化因子和生长因子基因的表达，导致细胞运输和激活的改变，从而损害伤口愈合。这些研究的长期目标是了解神经内分泌和炎症反应之间的应激相关变化的潜在机制，这些反应是导致伤口愈合改变的原因。该建议的目的是1)确定应激对伤口愈合早期趋化因子、促炎细胞因子和生长因子基因表达的模式和动力学的影响，2)确定在伤口愈合过程中调节促炎细胞因子、趋化因子和生长因子基因表达的应激诱导的神经内分泌机制，以及3)确定雄烯二醇(DHEA的代谢物)的抗糖皮质激素作用的机制，并描述其调节促炎细胞因子(IL-1α、β和TNFα)、趋化因子(KC、IP10、MCP-1和MIP 1α)和生长因子(KGF、1α)的能力。血管内皮生长因子和转化生长因子β)基因表达作为一种治疗策略来改善应激个体的伤口愈合。该提案利用组织学、分子生物学和药理学的方法来解决具体目标。创伤愈合的体内研究伴随着糖皮质激素和AED(二羟基表雄酮的代谢物)对细胞转录因子和细胞因子表达的直接影响的体外研究。重复数天的束缚应激被用作应激范式，皮肤损伤将被用来确定愈合率以及在愈合期细胞因子和趋化因子的分布。随后的研究将使用体外方法，将从雌性小鼠分离的中性粒细胞和巨噬细胞与皮质酮孵育，以确定内毒素诱导的细胞因子和趋化因子释放的刺激以及对核因子-kappaβ的变化的影响。此外，AED对伤口愈合、细胞因子和趋化因子的产生以及转录因子NF-kappaβ的影响也将在体内进行研究。

DESCRIPTION (adapted from investigator's abstract): The hypothesis of this proposal is that physiologic changes associated with stress, down-regulate pro-inflammatory cytokine, chemokine and growth factor gene expression resulting in alterations in cellular trafficking and activation, thus impairing wound healing. The long term goal of these studies is to understand the mechanisms underlying stress-related changes between the neuroendocrine and inflammatory responses that are responsible for altered wound healing. The aims of the proposal are 1) to determine the influence of stress on the pattern and kinetics of chemokine, pro-inflammatory cytokine and growth factor gene expression during the early stages of wound healing, 2) to determine the stress-induced, neuro-endocrine mechanisms that regulate pro-inflammatory cytokine, chemokine and growth factor gene expression during wound healing and 3) to determine the mechanism of the anti-glucocorticoid actions of androstenediol (a metabolite of DHEA) and delineate its ability to regulate pro-inflammatory cytokines (IL-1 alpha and beta and TNF alpha), chemokines (KC, IP10, MCP-1 and MIP 1 alpha) and growth factor (KGF, VEGF and TGF beta )gene expression as a therapeutic strategy to improve wound healing in stressed individuals. The proposal makes use of histological, molecular biology and pharmacological approaches to address the specific aims. The in vivo study of wound healing is accompanied by in vitro studies of the direct effect of glucocorticoids and AED (a metabolite of dihydroxyepiandrosterone) on cellular expression of transcription factors and cytokines. Restraint stress repeated over several days is to be used as a stress paradigm, skin wounding will be used to determine the rate of healing and the profile of cytokines and chemokines during the healing period. Subsequent studies will use an in vitro approach in which neutrophils and macrophages isolated from female mice will be incubated with corticosterone to determine the effect of LPS induced stimulation of cytokine and chemokine release and on changes in NF-kappa beta. In addition, the influence of AED on wound healing, cytokine and chemokine production and transcription factor NF-kappa beta will also be addressed in vivo.