Inflammation after traumatic brain injury

描述：(逐字摘自申请者摘要)创伤性脑损伤(TBI) 引发一连串的炎症过程，可能会加剧 最初的伤势。最近的实验数据表明，创伤后 温度控制显著影响炎症反应， 包括多形核白细胞(PMNL)的堆积和诱导 一氧化氮合酶活性。拟议的研究将建立在这些基础上 以前的结果，并研究了细胞、生化和分子 体温敏感型炎症事件的潜在机制 TBI。针对具体问题提出了三个具体目标 关于这一调查问题。在第一个具体目标中，实验将 重点关注创伤后炎症的诱因，重点是炎症 细胞因子。这些调查将确定受伤的重要性 颅脑损伤后细胞因子反应的严重程度及其影响因素 时间，这些创伤后温度手法的影响 炎症诱导剂。在第二个目标中，我们将调查主要的 这些炎症分子对应激信号的作用，包括p38 丝裂原活化蛋白激酶、转录因子、核因子-kB以及 内皮细胞黏附分子(ICAM-1、P-选择素)的表达。这些 研究被认为是重要的，因为它们将决定 创伤后体温过低对生产和释放的影响 在促炎细胞因子中，对次级信号转导有主要作用 小路。在最终目标中，我们将确定不同的影响 体温过低对炎症级联反应的选择性影响。为了达到这个目的， 转基因和基因敲除小鼠将在常温和 体温过低。这些研究将以调查损伤过程为目标 在AIMS I和II中，评估急性和更长期的结构性和 低温保护中特定损伤过程的功能后果。 建立了酶联免疫吸附试验组织病理学分析的定量方法 原位杂交，分子技术，以及大量的 在大鼠和小鼠的行为任务中，将用于补充总体 求婚。这种创伤研究的新方法应该会提供重要的数据 关于炎症过程和温度之间的相互作用。

DESCRIPTION: (Verbatim from applicant's abstract) Traumatic brain injury (TBI) initiates a cascade of inflammatory processes that can serve to exacerbate the initial injury. Recent experimental data indicate that post-traumatic temperature manipulations significantly influence the inflammatory responses, including the accumulation of polymorphonuclear leukocytes (PMNL) and inducible nitric oxide synthase activity. The proposed studies will build on these previous results and investigate the cellular, biochemical, and molecular mechanisms underlying the temperature-sensitive inflammatory events seen after TBI. Three specific aims are proposed that focus on specific questions regarding this investigative issue. In the first specific aim, experiments will focus on inducers of post-traumatic inflammation, with emphasis on inflammatory cytokines. These investigations will determine the importance of injury severity on the cytokine response to TBI as well as determining for the first time the effects of post-traumatic temperature manipulations of these inflammatory inducers. In the second aim, we will investigate the primary actions of these inflammatory molecules on stress signals, including p38 mitogen-activated protein kinase, the transcriptional factor, NF-kB, as well as the expression of endothelial adhesion molecules (ICAM-1, P-selectin). These studies are felt to be important because they will determine whether post-traumatic hypothermia in contrast to affecting the production and release of the pro-inflammatory cytokines, have a primary effect on secondary signaling pathways. In the final aim, we will determine the differential effects of hypothermia on selective aspects of the inflammatory cascade. For this aim, transgenic and knockout mice will be investigated under normothermic and hypothermic conditions. These studies will target injury processes investigated in Aims I and II and assess both the acute and more chronic structural and functional consequences of specific injury processes in hypothermia protection. Established quantitative methods of ELISA's, histophatological analysis, in situ hybridization, molecular techniques, as well as a large battery of behavioral tasks in rats and mice, will be used to complement the overall proposal. This new approach to trauma research should provide important data concerning interactions between inflammatory processes and temperature.