DISREGULATION OF NEURONAL GSK-3BETA BY PAF

描述（改编自申请人摘要）：血小板活化因子 (PAF)是一种生物活性磷脂，在中枢神经系统中起着多种作用。 神经系统（CNS）。一些病理事件，包括癫痫， 缺血和炎症反应导致PAF在突触中的积聚。 在这种情况下，PAF可以作为神经元损伤的介质。含量超标 PAF也可能通过抑制中枢神经系统的正常发育， 神经元迁移（例如，在Miller-Dieker的上下文中 无脑畸形）。 我们的初步研究表明PAF可以上调 糖原合成酶激酶3-β（GSK-3b）在原代神经元中的表达。这可能是 与PAF对神经元存活和神经元迁移的影响有关， GSK-3b与轴突重塑和神经元凋亡的调节有关。 神经细胞骨架，也因为GSK-3b的激活（过度表达） 已证实可导致PC 12细胞凋亡。因此我们 推测PAF对GSK-3b作用可能与其神经毒性 活性及其破坏神经元迁移的能力。建议的研究 在本申请中，旨在实验性地测试该假设。第一、 分子机制，这有助于PAF介导的激活， 神经元GSK-3b将被描绘（目的1）。第二，实验将 进行;检验GSK-3b激活是 PAF介导的神经毒性（目的2）。最后，将进行研究， 确定GSK-3b激活是否也是PAF介导的 破坏神经元迁移（目的3）。综合起来，这些实验 有望为GSK-3b活性的调节提供新的见解， 神经元，并进入GSK-3b可能在介导PAF的作用， 神经元存活和神经元迁移。

DESCRIPTION (adapted from applicant's abstract): Platelet activating factor (PAF) is a bioactive phospholipid which plays a variety of roles in the central nervous system (CNS). A number of pathologic events, including seizures, ischemia and inflammatory reactions lead to the synaptic accumulation of PAF. In this setting, PAF can act as a mediator of neuronal injury. Excessive levels of PAF may also interfere with the normal development of the CNS, by inhibiting neuronal migration (for example, in the context of Miller-Dieker lissencephaly). Our preliminary studies have shown that PAF can upregulate the activity of glycogen synthase kinase 3-beta (GSK-3b) in primary neurons. This may be relevant to PAF's effects on neuronal survival and neuronal migration because GSK-3b has been implicated in axonal remodeling and in the regulation of the neuronal cytoskeleton, and also because activation (over expression) of GSK-3b has been demonstrated to lead to apoptosis of PC12 cells. We therefore hypothesize that PAF's effects on GSK-3b may contribute both to its neurotoxic activity and to its ability to disrupt neuronal migration. The studies proposed in this application are intended to experimentally test this hypothesis. First, the molecular mechanisms, which contribute to PAF-mediated activation of neuronal GSK-3b, will be delineated (Aim 1). Second, experiments will be conducted; to test the hypothesis that GSK-3b activation is required for PAF-mediated neurotoxicity (Aim 2). Finally, studies will be performed to determine whether GSK-3b activation is also required for PAF-mediated disruption of neuronal migration (Aim 3). Taken together, these experiments are expected to provide new insights into the regulation of GSK-3b activity in neurons, and into the role that GSK-3b may play in mediating PAF's effects on neuronal survival and neuronal migration.