Identification of the Protein Kinases which Regulate Mammalian Synapse Formation

调节哺乳动物突触形成的蛋白激酶的鉴定

• 批准号: 7708270
• 负责人: SUZANNE PARADIS
• 金额: $ 15.79万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7708270
• 关键词: Applications Grants; Area; Award; Basic Science; Biological Assay; Brain; Cells; Cellular biology; Cocaine; Cognitive; Communication; Complement; Complex; Development; Disease; Drug Addiction; Drug Design; Drug Exposure; Emerging Technologies; Funding; Funding Mechanisms; Genes; Genetic; Glutamates; Goals; Hand; Hippocampus (Brain); Human; Investigation; Learning; Mediating; Mediator of activation protein; Memory; Microarray Analysis; Molecular; Mus; National Institute of Drug Abuse; Nervous system structure; Neuraxis; Neurons; Nucleus Accumbens; Phosphotransferases; Play; Process; Protein Kinase; RNA Interference; Relapse; Research; Role; Screening procedure; Set protein; Signal Transduction; Site; Speech; Structure; Symptoms; Synapses; System; Technology; Testing; Time; Transcript; addiction; base; density; drug craving; gene discovery; genome-wide; insight; knock-down; neural circuit; novel; novel strategies; public health relevance; response; synaptogenesis; therapeutic development; voltage clamp

DESCRIPTION (provided by applicant): Synapses are specialized sites of cell-cell contact that mediate communication between neurons in the nervous system. Much remains to be discovered about the molecular mechanisms that underlie formation of these critical structures in the mammalian central nervous system. Previously, we developed a novel, forward genetic, RNA-interference (RNAi)-based approach to identifying new molecules that regulate synapse formation. Currently, we are in the process of applying this technology to understanding the cell biology of drug addiction. Thus far, a number of kinases have been implicated in regulating synapse formation or function, lending support to the hypothesis that protein kinases have critical functions at the synapse. Further, activation of protein kinase signaling has been hypothesized to underlie changes in neuronal structure and synapses in response to drug exposure. Therefore, further investigation into the role of protein kinases in synapse formation is warranted. To this end, we propose to take a genome-wide approach to identify the full complement of protein kinases that are expressed at the time that synapses are forming in cultured mammalian neurons. Next, we will utilize our RNAi-based screening approach to ask which kinases are required for the formation of functional glutamatergic and/or GABAergic synapses. PUBLIC HEALTH RELEVANCE: A current hypothesis to explain the persistent features of drug addiction, including drug cravings and relapse, posits that changes in synaptic structure and neuronal connectivity underlie these features of the disease. Further, the function of protein kinases has been implicated in these changes in synaptic structure. Thus, a genome-wide approach to understanding the role of protein kinases in synapse formation and function as outlined in this proposal has the potential to yield important insights into the underlying causes of a subset of features of drug addiction.

描述（由申请人提供）：突触是介导神经系统中神经元之间通信的细胞-细胞接触的专门位点。关于哺乳动物中枢神经系统中这些关键结构形成的分子机制仍有许多有待发现。以前，我们开发了一种新的，正向遗传，RNA干扰（RNAi）为基础的方法，以确定新的分子，调节突触的形成。目前，我们正在应用这项技术来了解药物成瘾的细胞生物学。到目前为止，许多激酶都参与调节突触的形成或功能，支持蛋白激酶在突触中具有关键功能的假设。此外，蛋白激酶信号传导的激活已被假设为响应于药物暴露的神经元结构和突触变化的基础。因此，进一步研究蛋白激酶在突触形成中的作用是必要的。为此，我们建议采取全基因组的方法，以确定完整的蛋白激酶的表达时，突触在培养的哺乳动物神经元形成的补充。接下来，我们将利用我们的基于RNAi的筛选方法来询问哪些激酶是形成功能性谷氨酸能和/或GABA能突触所必需的。公共卫生相关性：目前解释药物成瘾的持续特征（包括药物渴望和复发）的假设认为，突触结构和神经元连接的变化是疾病这些特征的基础。此外，蛋白激酶的功能已被牵连在这些突触结构的变化。因此，一个全基因组的方法来理解蛋白激酶在突触形成和功能中的作用，如本提案所概述的，有可能产生重要的见解的潜在原因的一个子集的功能的药物成瘾。