Cellular Indicators Of Neuronal Insult

脑内炎症细胞的局部激活可能导致急性脑损伤后的神经元死亡以及更进行性的退变过程。在这个网络中，不同的细胞交流和调节免疫和炎症反应的启动、传播和抑制的复杂过程。通过常驻免疫细胞网络以及神经元和胶质细胞之间的细胞间相互作用，当受到侮辱时，会发生一连串的反应，发出可能导致神经元死亡的信号。这个项目的目的是确定神经胶质细胞反应的关键特征，它可能导致或加剧正在进行的神经元死亡过程。这些特征不仅包括单个细胞的反应，还包括可能影响这种反应结果的细胞外环境。我们已经确定，大脑中的炎症反应与外周的炎症反应大致相同。作为一种宿主防御反应，它起到保护大脑的作用，然而，当反应变得失调时，这可能会导致不良事件。在这一框架下，我们已经报道，小胶质细胞不仅在损伤反应的初始阶段起关键作用，而且在损伤后的修复过程中也是至关重要的。在这个过程中，肿瘤坏死因子的上调和小胶质细胞通过细胞周期过程的调节似乎都是关键因素。在有机金属三甲基锡诱导的神经元死亡的活跃过程中，我们描述了大量新神经元的生成以供替代。修复的程度是相当高的，并且发生在高度炎症信号的环境中。通过这个网络，各种细胞进行交流，并调节免疫和炎症反应的启动、传播和抑制的复杂过程。在过去的一年里，我们使用这种化学诱导的海马神经元损伤模型继续我们的研究，除了鉴定早期发生在小胶质细胞中的形态和细胞反应外，还表征了在神经元损伤证据之前发生的分子信号。这些研究支持“炎症”在为神经元修复提供刺激环境方面的积极作用，我们计划继续使用基因表达水平的基因芯片分析和其他技术，如细胞免疫组织化学技术来定位负责修复和再生的细胞。这类研究有望确定促进内源性神经发生的关键信号条件，这可能适用于急性损伤，如中风、头部创伤和更进行性神经退行性疾病的治疗方法。

Local activation of inflammatory cells in the brain may contribute to neuronal death that occurs following acute brain injury as well as more progressive degenerative processes. In this network, various cells communicate and regulate complex processes of initiation, propagation, and suppression of immune and inflammatory responses. Through the resident immune cell network and the cell-cell interactions between the neurons and the glia a cascade of responses occur upon insult that signal events that may lead to neuronal death. The purpose of this project is to identify the critical features of the glia response that may either cause or exacerbate an ongoing process of neuronal death. These features include not only the individual cell response but also the extracellular environment that may influence the outcome of such responses. We have determined that the inflammatory response in the brain serves much the same was as that in the periphery. As a host defense response it serves to protect the brain however, when the response becomes dysregulated this can lead to adverse events. Under this framework we have reported that microglia cells are critical not only in the initial phase of the damage response but also in the repair process following injury. During this process both the up-regulation of tumor necrosis factor and the regulation of microglia cells via cell cycle processes appear to be critical factors . In the active process of neuronal death induced by the organo-metal, trimethyltin, we characterized a dramatic generation of new neurons for replacement. The level of repair is substantial and occurs within an environment of high inflammatory signals. Through this network, various cells communicate and regulate complex processes of initiation, propagation, and suppression of immune and inflammatory responses. Over the past year we have continued our studies using this chemical-induced model of hippocampal neuronal damage and have characterized the molecular signals that occur prior to evidence of neuronal insult in addition to identifying the morphological and cellular responses that occur early in the microglia. These studies support a positive role for "inflammation" in providing a stimulating environment for neuronal repair and we plan to continue our examination of this model at the gene expression level using cDNA microarray analysis and other techniques as cell as immmunohistochemical techniques to localize the cells responsible for repair and regeneration. Such studies offer the promise of identifying the critical signal conditions to enhance endogenous neurogenesis which may be applicable to acute injuries such as stroke, head trauma and therapeutic approaches for more progressive neurodegenerative disorders.