Neurotrophin Actions in the Injured Brain

描述(由申请人提供)：神经营养素长期以来一直被认为是 通过支持许多神经元群体的生存和分化 与trk酪氨酸激酶受体的相互作用。我们最近的研究 实验室和其他研究人员已经证明，神经营养因子也可以诱导细胞 通过p75受体死亡。因此，无论神经元是存活还是死亡 对神经营养因子的作用可能取决于信号通路的平衡 这些不同的受体。尽管p75在许多中枢神经系统中瞬时表达 神经元群体在发育过程中，这种受体并没有广泛表达 在正常的成人大脑中。然而，损伤后脑组织中p75的表达 可以在许多神经元中检测到，这表明这个基因的上调 受体可能是损伤或应激反应的一部分。自NGF产生以来 也是由多种类型的损伤在大脑中诱导的，我们假设NGF 与p75相互作用，消除因损伤而受损的神经元。 在这项拨款申请中，我们建议调查p75受体是否 匹罗卡品诱导的活体死亡神经元上的表达 癫痫发作。我们将比较正常癫痫发作后死亡神经元的数量 用p75-/-小鼠评估该受体在介导神经元中的作用 损失。这些活体研究将伴随着对海马体的研究。 目的：探讨p75介导的神经元死亡机制。 因此，这些研究的目标是确定p75神经营养因子的作用。 海马神经元中介导细胞死亡的受体，特别是在 脑部损伤的情况。

DESCRIPTION (provided by the applicant): Neurotrophins have long been known to support the survival and differentiation of many neuronal populations through interactions with the trk tyrosine kinase receptors. Recent studies from our laboratory and others have demonstrated that neurotrophins can also elicit cell death via the p75 receptor. Thus, whether a neuron survives or dies in response to neurotrophins may depend on a balance of signaling pathways activated by these different receptors. Although p75 is transiently expressed in many CNS neuronal populations during development, this receptor is not widely expressed in the normal adult brain. However, after damage in the brain expression of p75 can be detected in numerous neurons, suggesting that upregulation of this receptor may be part of an injury or stress response. Since production of NGF is also induced in the brain by many types of damage, we hypothesize that NGF interacts with p75 to eliminate neurons that are compromised by damage. In this grant application we propose to investigate whether the p75 receptor is expressed on dying neurons in vivo as a consequence of pilocarpine-induced seizures. We will compare the number of dying neurons after seizure in normal mice with p75-/- mice to assess the role of this receptor in mediating neuronal loss. These in vivo studies will be accompanied by studies on hippocampal neurons in vitro to investigate the mechanisms of p75-mediated neuronal death. Thus, the goal of these studies is to define the role of the p75 neurotrophin receptor in mediating cell death in hippocampal neurons, particularly under conditions of brain injury.