High Throughput Screen for Small Molecule Probes for Neural Network Development

用于神经网络开发的小分子探针的高通量筛选

• 批准号: 8661303
• 负责人: Richard L Huganir
• 金额: $ 40.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-18 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8661303
• 关键词: Animals; Autistic Disorder; Automation; Biological; Biological Assay; Biological Neural Networks; Brain; Chemicals; Collection; Data; Data Set; Defect; Dendrites; Development; Disease; Dose; Drug Targeting; Epilepsy; Equilibrium; Genes; Genetic; Goals; Image; Ion Channel; Knockout Mice; Lead; Length; Libraries; Light; Mental Retardation; Methods; Molecular; Neuraxis; Neurodevelopmental Disorder; Neuromuscular Junction; Neurons; Nuclear Receptors; Pathway interactions; Peptide Hydrolases; Peripheral Nervous System; Pharmaceutical Preparations; Phosphotransferases; Population; Process; Proteins; Reporting; Schizophrenia; Solubility; Staining method; Stains; Synapses; Testing; Therapeutic; Time; Toxic effect; Twin Multiple Birth; United States National Institutes of Health; base; density; high throughput screening; immunocytochemistry; in vitro activity; in vivo; insight; medical specialties; neuron development; response; scale up; small molecule; small molecule libraries; synaptogenesis; tool

DESCRIPTION (provided by applicant): Many major neurodevelopmental disorders, including autism, epilepsy and schizophrenia, are believed to the caused by aberrant synapse formation during brain development, resulting in an excess or deficit of certain classes of synapses. Our long term goal is to understand the molecular mechanisms of synapse formation in the central nervous system (CNS), with the aim of developing therapeutics for these devastating diseases. The process of synapse formation has been best characterized in the peripheral nervous system, where the complete loss of neuromuscular junctions has been reported for multiple single gene knockout mice. In the central nervous system, despite the presence of many proteins that show strong synaptogenic activity in vitro, genetic deletion of several of these proteins result in only subtle changes in synapse density limited to small populations of neurons. These results suggest that the synaptogenic machinery in the CNS is heavily redundant; a situation that makes it inefficient to apply traditional genetic approaches to study the problem. We believe that an unbiased chemical screen for determinants of synapse formation, with its potential to block or enhance key pathways and entire classes of genes, may present a more efficient approach to studying synaptogenic mechanisms in the CNS. In addition, the study may also generate small molecule probes that will be useful in perturbing synapse formation and excitatory-inhibitory balance in vivo. An excess or deficit of specific synapses has been hypothesized to underlie many neurodevelopmental disorders, but to date, these hypotheses have been difficult to prove due to the lack of tools to perturb the underlying network connectivity. We believe our proposal will remedy this situation, and at the same time generate a high impact dataset which will shed light on the mechanisms of synapse formation in the CNS.

描述(申请人提供)：许多主要的神经发育障碍，包括自闭症、癫痫和精神分裂症，被认为是由大脑发育过程中异常的突触形成引起的，导致某些类别的突触过剩或不足。我们的长期目标是了解中枢神经系统(CNS)突触形成的分子机制，目的是开发治疗这些毁灭性疾病的方法。突触形成的过程在外周神经系统中得到了最好的描述，在那里，有报道称在多个单基因敲除小鼠中，神经肌肉连接完全丧失。在中枢神经系统中，尽管存在许多在体外显示出很强的突触生成活性的蛋白质，但其中几个蛋白质的基因缺失只会导致仅限于少量神经元的突触密度的细微变化。这些结果表明，中枢神经系统中的突触形成机制是严重冗余的；这种情况使得应用传统的遗传学方法来研究这个问题是低效的。我们认为，对突触形成的决定因素进行无偏见的化学筛选，具有阻断或增强关键通路和整个基因类别的潜力，可能为研究中枢神经系统的突触发生机制提供了一种更有效的方法。此外，这项研究还可能产生有助于扰乱体内突触形成和兴奋-抑制平衡的小分子探针。特定突触的过多或不足被认为是许多神经发育障碍的基础，但到目前为止，由于缺乏干扰潜在网络连接的工具，这些假说很难得到证明。我们相信，我们的建议将纠正这种情况，同时产生一个高影响的数据集，将阐明中枢神经系统中突触形成的机制。