Discerning the role of p25 production in synaptic plasticity.

辨别 p25 产生在突触可塑性中的作用。

• 批准号: 7386677
• 负责人: Paola Giusti
• 金额: $ 3.17万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386677
• 关键词: Acute; Address; Binding; Biological; Calcium; Calpain; Cell Death; Chemicals; Chronic; Condition; Cyclin-Dependent Kinase 5; Data; Development; Dose; Event; Generations; In Vitro; Knock-in Mouse; Lead; Learning; Long-Term Potentiation; Mediating; Memory; Molecular; Mus; Nerve Degeneration; Neurons; Physiological; Play; Production; Protein Overexpression; Proteins; Protocols documentation; Reading; Reagent; Resistance; Role; Source; Synaptic plasticity; cerebral atrophy; in vivo; mouse model; mutant; neuron loss; neurotoxic; novel; research study

DESCRIPTION (provided by applicant): Our lab studies the function of cyclin-dependent kinase 5 (Cdk5) in neuronal development and neurodegeneration. Recent evidence suggests an additional role for Cdk5 in synaptic plasticity and learning and memory. Cdk5 is activated through binding to its neuronal-specific activator p35. Studies up until this point have shown that neurotoxic conditions result in the cleavage of p35 into p25 in vitro and subsequent cell death. Moreover, overexpression of p25 in vitro and in vivo, have been associated with neuronal cell death and brain atrophy, suggesting that overactivation of Cdk5 by p25 is detrimental. We now have novel data that chemical induction of long-term potentiation (LTP) can generate p25 without resulting in cell death. The experiments outlined herein seek to address the relationship between p25 production through LTP induction and synaptic plasticity using both in vitro and in vivo studies. Additionally, we are generating a knock-in mouse model which expresses a mutant form of p35 that is resistant to calpain-mediated cleavage to better address the physiological functions of p35 and p25 in neurodegeneration, synaptic plasticity and learning and memory. These experiments have the potential of enhancing our understanding of the molecular events involved in neurodegeneration, synaptic plasticity and learning and memory, and could lead to the development of new therapies.

描述（由申请人提供）：我们的实验室研究细胞周期蛋白依赖性激酶5 （Cdk5）在神经元发育和神经变性中的功能。最近的证据表明，Cdk5在突触可塑性和学习记忆中起着额外的作用。Cdk5通过与其神经元特异性激活剂p35结合而激活。到目前为止的研究表明，神经毒性条件导致p35在体外裂解为p25，随后导致细胞死亡。此外，p25在体外和体内的过度表达与神经元细胞死亡和脑萎缩有关，这表明p25过度激活Cdk5是有害的。我们现在有新的数据表明，化学诱导的长期增强（LTP）可以产生p25而不导致细胞死亡。本文概述的实验旨在通过体外和体内研究解决通过LTP诱导产生p25与突触可塑性之间的关系。此外，我们正在构建一种敲入小鼠模型，该模型表达p35的一种突变形式，可以抵抗calpain介导的裂解，以更好地解决p35和p25在神经变性、突触可塑性和学习记忆中的生理功能。这些实验有可能增强我们对神经退行性变、突触可塑性和学习记忆的分子事件的理解，并可能导致新疗法的发展。