DISREGULATION OF NEURONAL GSK-3BETA BY PAF

PAF 对神经元 GSK-3BETA 的失调

• 批准号: 6540292
• 负责人: Stephen Dewhurst
• 金额: $ 27.91万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6540292
• 关键词: PC12 cells; animal tissue; apoptosis; cell growth regulation; cell migration; cytokine receptors; enzyme activity; enzyme inhibitors; glycogen synthase; neurons; neurotoxicology; phospholipids; phosphorylation; platelet activating factor; protein kinase; receptor expression

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.

描述（改编自申请人的摘要）：血小板激活因子 (PAF) 是一种生物活性磷脂，在中枢神经系统中发挥多种作用。 神经系统（CNS）。许多病理事件，包括癫痫发作、 缺血和炎症反应导致 PAF 的突触积聚。 在这种情况下，PAF 可以充当神经元损伤的介质。水平过高 PAF 还可能通过抑制中枢神经系统的正常发育来干扰 神经元迁移（例如，在 Miller-Dieker 无脑畸形）。 我们的初步研究表明，PAF 可以上调 原代神经元中的糖原合酶激酶 3-β (GSK-3b)。这可能是 与 PAF 对神经元存活和神经元迁移的影响有关，因为 GSK-3b 与轴突重塑和神经元的调节有关 神经元细胞骨架，也因为 GSK-3b 的激活（过度表达） 已被证明可导致 PC12 细胞凋亡。我们因此 假设 PAF 对 GSK-3b 的影响可能导致其神经毒性 活性及其破坏神经元迁移的能力。提出的研究 在本申请中旨在通过实验检验这一假设。第一的， 分子机制，有助于 PAF 介导的激活 将描绘神经元 GSK-3b（目标 1）。其次，将进行实验 实施;检验 GSK-3b 激活所需的假设 PAF 介导的神经毒性（目标 2）。最后，将进行研究 确定 PAF 介导是否也需要 GSK-3b 激活 破坏神经元迁移（目标 3）。综合起来，这些实验是 预计将为 GSK-3b 活性的监管提供新的见解 神经元，并了解 GSK-3b 在介导 PAF 的作用中可能发挥的作用 神经元存活和神经元迁移。