Novel control of CDK5 function in the brain

大脑中 CDK5 功能的新控制

• 批准号: 9261610
• 负责人: Yue Feng
• 金额: $ 33.92万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9261610
• 关键词: Affect; Alzheimer' s Disease; Amygdaloid structure; Attenuated; Brain; Brain Diseases; Cell Cycle Progression; Cognition Disorders; Cyclin-Dependent Kinase 5; Data; Dendritic Spines; Development; Disease; Embryo; Epilepsy; Epileptogenesis; Genes; Goals; Hippocampus (Brain); Impairment; Inflammatory Response; Knowledge; Learning; Mediating; Memory; Mitotic; Modeling; Molecular; Mus; Neurodegenerative Disorders; Neuronal Differentiation; Neurons; Neurotransmitter Receptor; Neurotransmitters; Normal Cell; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Pharmacology; Phenotype; Phosphorylation; Physiological; Play; Predisposition; Proteins; Receptor Signaling; Regulation; Reporting; Research; Role; Schizophrenia; Seizures; Serine; Severities; Signal Transduction; Stroke; Synapses; Synaptic plasticity; Testing; Threonine; Up-Regulation; base; conditioned fear; cyclooxygenase 2; density; fear memory; insight; knock-down; member; migration; neuron development; neurotoxic; novel; novel strategies; phosphoproteomics; postnatal; public health relevance; response; spatial memory; synaptic function

 DESCRIPTION (provided by applicant): Cyclin-dependent kinase 5 (CDK5) is a key player that governs brain development and function by phosphorylation of serine and threonine residues on diverse protein targets. Unlike other CDK members, CDK5 does not control normal cell cycle progression, but plays prominent roles in controlling neuronal migration, dendritic spine density, neurotransmitter receptor signaling, and activity-dependent synaptic plasticity in post-mitotic brain neurons. Moreover, dysregulation of CDK5 is reported in an increasing list of brain disorders, including Alzheimer's disease, schizophrenia, stroke, and epilepsy. Activation of CDK5 depends on the available amount of p35 or p39, two non-cyclin activators encoded by the CDK5R1 and CDK5R2 gene, respectively. Previous studies have overwhelmingly focused on the function of p35 in controlling CDK5 signaling, partly due to the severe phenotype of p35-/- mice in embryonic brain development and the involvement of p35 in neurotoxic damage. Why postnatal brain neurons express abundant p39 is not understood and unfortunately understudied. Importantly, emerging evidence has revealed differential functions of p35 and p39 in normal and diseased brains. However, molecular mechanisms that regulate CDK5 activator expression in neurons, which in turn govern CDK5 activity, are vastly unknown. In particular, which CDK5 activator is responsible for modulating CDK5 activity and promoting neuronal and synapse development is undefined. Moreover, whether and how neuronal activation regulates CDK5 activator expression thus underlie CDK5-dependent brain function is an intriguing question that remains to be answered. This proposal focuses on elucidating the regulation and function of the CDK5R2 gene that encodes p39. Based on our preliminary data, we hypothesize that selective regulation of p39 is responsible for modulating CDK5 activity during neuronal differentiation and activation, which directs CDK5 signaling toward specific targets to control synaptic development and brain function in response to physiological and pathological challenges. We propose the following Specific Aims to test this hypothesis: (1) To determine molecular mechanisms that regulate p39 expression during neuronal development and in response to neuronal activity changes; (2) to determine the function and targets of p39 in CDK5 signaling and dendritic spine/synapse development; (3) To determine the role of p39 in learning and memory formation and epileptogenesis.

 描述（由申请人提供）：细胞周期蛋白依赖性激酶5（CDK 5）是一种关键参与者，通过磷酸化不同蛋白质靶点上的丝氨酸和苏氨酸残基来控制大脑发育和功能。与其他CDK成员不同，CDK 5不控制正常的细胞周期进程，但在控制有丝分裂后脑神经元中的神经元迁移、树突棘密度、神经递质受体信号传导和活性依赖性突触可塑性中起重要作用。此外，在越来越多的脑疾病中报道了CDK 5的失调，包括阿尔茨海默病、精神分裂症、中风和癫痫。CDK 5的激活取决于p35或p39的可用量，这两种非细胞周期蛋白激活剂分别由CDK 5 R1和CDK 5 R2基因编码。以前的研究主要集中在p35在控制CDK 5信号传导中的功能，部分原因是p35-/-小鼠在胚胎脑发育中的严重表型以及p35参与神经毒性损伤。为什么出生后的大脑神经元表达丰富的p39还不清楚，不幸的是，研究不足。重要的是，新出现的证据揭示了p35和p39在正常和患病大脑中的不同功能。然而，调节神经元中CDK 5激活剂表达的分子机制，这反过来又控制CDK 5活性，是非常未知的。具体而言，哪种CDK 5激活剂负责调节CDK 5活性并促进神经元和突触发育尚未确定。此外，神经元激活是否以及如何调节CDK 5激活剂的表达，从而成为CDK 5依赖性脑功能的基础，这是一个有趣的问题，仍有待回答。该提案的重点是阐明编码p39的CDK 5 R2基因的调控和功能。基于我们的初步数据，我们假设p39的选择性调节负责调节神经元分化和激活期间的CDK 5活性，其将CDK 5信号传导导向特定靶点以控制突触发育和脑功能以响应生理和病理挑战。我们提出以下具体目标来验证这一假设：（1）确定在神经元发育过程中调节p39表达的分子机制，以及对神经元活动变化的反应;（2）确定p39在CDK 5信号传导和树突棘/突触发育中的功能和靶点;（3）确定p39在学习记忆形成和癫痫发生中的作用。