CDK5 ACTIVATORS IN NEURITE POLARIZATION AND DEGENERATION

神经突极化和退化中的 CDK5 激活剂

• 批准号: 6440177
• 负责人: ADRIANA B. FERREIRA
• 金额: $ 3.9万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6440177
• 关键词: South America; amyloid proteins; antisense nucleic acid; axon; cellular polarity; cooperative study; cyclin dependent kinase; dendrites; developmental neurobiology; enzyme activity; enzyme mechanism; gene expression; gene targeting; genetically modified animals; guanosinetriphosphatases; immunocytochemistry; immunofluorescence technique; intracellular transport; laboratory mouse; mitogen activated protein kinase; neural degeneration; neurons; pyramidal cells; synaptogenesis; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant) Cyclin-dependent kinase 5 (Cdk5), a small serine-threonine kinase is required for proper development of the mammalian nervous system, and abnormal activation of this kinase is involved in the pathogenesis of cytoskeletal abnormalities and neuronal death in neurodegenerative disorders. To be activated, Cdk5 has to associate with regulatory subunits, such as p35 or p39. The experiments of the present proposal are directed to analyze the participation of these two highly related Cdk5 activators in neuronal polarization and in B-amyloid induced neurodegeneration. The specific hypotheses to be tested are that: 1) p35 and p39 have different expression patterns and subcellular localization, targeting Cdk5 to different substrates and hence having different functional roles during neuronal development. In this regard, we specifically propose that p35 is mainly involved in the regulation of cytoskeletal dynamics during axon formation, while p39 in synaptogenesis; and 2) Activation of the MAPK pathway by extracellular matrix molecules, such as laminin, or by B-amyloid enhances Cdk5 activity by promoting the synthesis of p35 and/or p39. These experiments will be carried out using as a model system cultured hippocampal pyramidal and several state of the art techniques in cellular and molecular biology. The results that we expect to obtain will certainly contribute to a better understanding of the mechanisms underlying neurite polarization and degeneration in central neurons.

描述（由申请人提供） 需要细胞周期蛋白依赖性激酶 5 (Cdk5)，一种小型丝氨酸-苏氨酸激酶 用于哺乳动物神经系统的正常发育和异常激活 该激酶参与细胞骨架异常的发病机制 和神经退行性疾病中的神经元死亡。要激活，Cdk5 必须 与调节亚基相关，例如 p35 或 p39。的实验 本提案旨在分析这两个高度重视的参与情况 神经元极化和 B-淀粉样蛋白诱导中相关的 Cdk5 激活剂 神经变性。要检验的具体假设是：1）p35 和 p39有不同的表达模式和亚细胞定位、靶向 Cdk5针对不同的底物，因此在过程中具有不同的功能作用 神经元发育。对此，我们特别建议p35是 主要参与轴突过程中细胞骨架动力学的调节 p39 参与突触发生； 2) MAPK 通路的激活 通过细胞外基质分子，例如层粘连蛋白，或通过 B-淀粉样蛋白增强 Cdk5 活性通过促进 p35 和/或 p39 的合成来实现。这些实验 将使用培养的海马锥体作为模型系统进行 细胞和分子生物学中的几种最先进的技术。这 我们期望获得的结果肯定会有助于更好的 了解神经突极化的机制和 中枢神经元退化。