CENTRAL NERVOUS SYSTEM DYSFUNCTION IN SHOCK AND TRAUMA

休克和创伤中的中枢神经系统功能障碍

• 批准号: 2177533
• 负责人: TRACY K. MCINTOSH
• 金额: $ 24.47万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-06-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2177533
• 关键词: CENTRAL; NERVOUS; SYSTEM; DYSFUNCTION; SHOCK

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.

描述：（改编自申请人的摘要）目标 这些研究是：1）阐明潜在的分子机制 脑强啡肽/κ阿片受体系统在介导 中枢神经系统对低血压的反应； 2）表征时间和区域 立即早期基因、应激蛋白和细胞因子的改变 大脑中的表达并将这些变化与基因表达相关联 对于阿片肽以及心血管和组织学反应 出血； 3）表征存在和区域激活 大脑中的程序性细胞死亡； 4) 促进 改进分子和药物治疗的发展 接近震惊。初步研究表明 内源性阿片类药物，尤其是强啡肽，似乎参与了 失血性休克期间心血管功能的中枢调节。 分子研究将沿着这条线继续进行，并选择 确定了大脑功能障碍的区域。调查人员将调查 k-阿片受体拮抗剂的治疗效果，也不是 二诺托菲明，钙通道阻滞剂，(s)-emopamil，IL-1 受体拮抗剂 IL1-RA 和 TNFa 抗体单独或组合 组合。这些研究旨在增强目前对 低血压和低血流状态的分子后遗症 休克和创伤，以促进更有效的发展 治疗休克的药物和基因治疗方法。