Signaling Scaffolds and Survival in Stroke

描述（由申请人提供）：为什么成熟的中枢神经系统（CNS）中的神经元在损伤后死亡？白色物质缺血（中风）导致轴突损伤，然后在大多数情况下导致CNS神经元死亡。因此，例如，缺血性视神经病变导致视网膜神经节细胞（RGC，一种CNS神经元）功能障碍和死亡，以及永久性视力丧失。 虽然许多细胞死亡和凋亡的下游分子途径正在深入研究中，但调控轴突损伤后存活和轴突再生的上游信号尚不清楚。 最近的证据表明，RGC在轴突损伤后死亡有两个原因：它们与靶源性营养信号切断，并且它们对这些信号的反应变得不那么灵敏。提高环磷酸腺苷（cAMP）可以增强营养反应，存活和再生，但信号转导途径仍在很大程度上未研究。在这里，我们将使用啮齿动物视网膜和视神经作为CNS神经元及其轴突，白色物质通路的模型系统，分别和测试的假设，间隔化信号的支架蛋白称为AKAP家族调节生存和再生信号在视神经中的白色物质中风的新模型。在三个具体目标中，我们将（1）鉴定负责原代神经元中cAMP信号传导的特异性腺苷酸环化酶~（2）鉴定由cAMP增强并有助于神经元存活和再生的特异性AKAP相关信号通路~和（3）确定在体内操纵AKAP介导的信号体是否调节缺血性轴突损伤后的体内神经元存活和再生。我们希望通过这些实验来确定缺血性轴突损伤后RGC存活失败的分子基础，并最终开发新的治疗方法来维持白色物质缺血后CNS神经元的存活。

DESCRIPTION (provided by applicant): Why do neurons in the mature central nervous system (CNS) die after injury? White matter ischemia (stroke) leads to axon injury and then in most cases to death of CNS neurons. Thus, for example, ischemic optic neuropathy leads to retinal ganglion cell (RGC, a type of CNS neuron) dysfunction and death, and permanent loss of vision. Although many of the downstream molecular pathways of cell death and apoptosis are under intensive study, the upstream signals that regulate survival and axon regeneration after axon injury are not known. Recent evidence suggests that RGCs die after axon injury for two reasons: they are cut off from target-derived trophic signals, and they become less responsive to such signals. Trophic responsiveness, survival and regeneration can be enhanced by elevating cyclic AMP (cAMP), but the signal transduction pathways remain largely unstudied. Here we will use the rodent retina and optic nerve as a model system for CNS neurons and their axonal, white matter pathways, respectively, and test the hypothesis that compartmentalized signaling on a family of scaffold proteins called AKAPs regulate survival and regeneration signaling in a novel model of white matter stroke in the optic nerve. In three Specific Aims, we will (1) identify the specific adenylyl cyclases responsible for cAMP signaling in primary neurons~ (2) identify the specific AKAP-related signaling pathways potentiated by cAMP and contributing to neuronal survival and regeneration~ and (3) determine whether manipulating AKAP-mediated signalosomes in vivo regulates neuronal survival and regeneration in vivo after ischemic axon injury. We hope through these experiments to determine the molecular basis for the failure of RGC survival after ischemic axon injury, and ultimately to develop new treatments to maintain CNS neuronal survival after white matter ischemia.