Identify functional modulators of ionotropic neurotransmitter receptors in brain

描述：NIH U01的提案标题是“识别脑中离子型神经递质受体的功能调节剂”。神经回路的失调导致各种类型的神经系统疾病，包括癫痫、精神发育迟滞、自闭症和共济失调。神经回路是由神经元通过神经递质在突触处相互通信构成的。因此，控制突触传递对人类健康至关重要。神经递质与神经递质受体结合并激活神经递质受体以传递峰电位或调节突触传递。尽管编码神经递质受体的基因在过去25年中被克隆，但最近发现了几个神经递质受体功能调节剂或辅助亚基的例子。功能调节剂的存在给研究人员带来了通过在异源细胞中单独表达受体来表征受体的繁琐而耗时的任务。然而，传统的筛选方法（包括蛋白质组学方法和功能克隆方法）的技术问题是鉴定功能调节剂的关键障碍。因此，我们需要开发新的方法来鉴定新的受体调节剂。在这个建议中，使用我们的新的高通量筛选跨膜ORF的集合，我们将确定阳离子型神经递质受体的功能调节剂。同时，我们将研究调节剂在受体相互作用，运输和通道特性中的作用。因此，这种无偏见的、全基因组的、敏感的筛选方法将对许多研究学科产生深远的影响。

DESCRIPTION: The title of this proposal for the NIH U01 is "Identify functional modulators of ionotropic neurotransmitter receptors in brain". Dysregulation of neural circuits causes various types of neurological disorders including epilepsy, mental retardation, autism and ataxia. Neural circuits are constructed by neurons that communicate each other at synapses through neurotransmitters. Therefore, controlling synaptic transmission is crucial for human health. Neurotransmitters bind to and activate neurotransmitter receptors to transfer spike or to modulate synaptic transmission. Whereas genes encoding neurotransmitter receptors had been cloned last 25 years, recently several examples of functional modulators or auxiliary subunits of neurotransmitter receptors were identified. The existence of functional modulators burdens researchers with the cumbersome and time-consuming task of characterizing receptors by expressing receptor alone in heterologous cells. However, a critical barrier to the identification f functional modulators is technical concerns in traditional screening including proteomic approach and functional cloning approach. Therefore, we need to develop new methods for the identification of novel receptor modulators. In this proposal, using our novel high-throughput screening using transmembrane ORF collections, we will identify functional modulators of cationic ionotropic neurotransmitter receptors. Simultaneously, we will examine roles of modulators in receptor interaction, trafficking and channel properties. This unbiased, genome-wide, sensitive screening method will therefore have a deep impact in many research disciplines.