CENTRAL NERVOUS SYSTEM DYSFUNCTION IN SHOCK AND TRAUMA

描述：(改编自申请人的摘要)目标 主要研究内容如下：1)阐明致病的分子机制。 脑强啡肽/kappa阿片受体系统在介导中枢神经系统损伤中的作用 中枢神经系统对低血压的反应；2)表征颞叶和区域 即刻早期基因、应激蛋白和细胞因子的变化 在大脑中表达，并将这种变化与基因表达相关联 阿片肽与心血管和组织学反应 到出血；3)表征病变的存在和局部激活 大脑中的程序性细胞死亡；以及4)促进 改良的分子和药物治疗方法研究进展 应对冲击的方法。初步研究证明， 内源性阿片类药物，尤其是强啡肽，似乎参与了 失血性休克时心血管功能的中枢调节。 分子研究将继续沿着这条线进行，选择 确定了大脑功能障碍的区域。调查人员将检查 K-阿片受体拮抗剂NOR-1的治疗效果 钙通道阻滞剂联苯托吡亚胺(S)-伊莫帕米，IL-1 受体拮抗剂IL1-RA和抗TNFa抗体单独或联合应用 组合。这些研究是为了加强目前对 伴随低血压和低流量状态的分子后遗症 从而使休克和创伤更有效地培育发展 治疗休克的药理学和遗传治疗方法。

DESCRIPTION: (Adapted from the applicant's abstract) The objectives of the studies are: 1) to elucidate the molecular mechanisms underlying the role of brain dynorphin/kappa opiate receptor systems in mediating the CNS response to hypotension; 2) to characterize the temporal and regional alterations in immediate early gene, stress protein and cytokine expression in the brain and correlate such changes with gene expression for opiate peptides and with the cardiovascular and histologic response to hemorrhage; 3) to characterize the presence and regional activation of programmed cell death in the brain; and 4) to facilitate the development of improved molecular and pharmacologic therapeutic approaches to shock. Preliminary studies have documented that endogenous opiates, most notably dynorphin, appear to be involved in the central regulation of cardiovascular function during hemorrhagic shock. Molecular investigations will continue along this line with selected areas of brain dysfunction identified. The investigators will examine the therapeutic efficacy of the k-opioid receptor antagonist, nor- binaltorphimine, the calcium channel blocker, (s)-emopamil, the IL-1 receptor antagonist, IL1-RA, and the antibody to TNFa alone or in combination. The studies are to enhance current understanding of the molecular sequelae of hypotension and low flow states that accompany shock and trauma so as to foster the development of more effective pharmacologic and genetic therapeutic approaches to treating shock.