Identify functional modulators of ionotropic neurotransmitter receptors in brain

描述：NIH U01的这项提案的标题是“识别大脑中的离子型神经递质受体的功能调节器”。神经回路的失调会导致各种类型的神经疾病，包括癫痫、智力低下、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上相互通信构成的。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，以传递棘波或调节突触传递。虽然编码神经递质受体的基因在过去25年里已经被克隆，但最近发现了几个神经递质受体的功能调节器或辅助亚单位的例子。功能调节剂的存在给研究人员带来了繁琐和耗时的任务，即通过在异种细胞中单独表达受体来表征受体。然而，在传统的筛选方法中，包括蛋白质组学方法和功能克隆方法在内的技术问题是鉴定功能调节子的关键障碍。因此，我们需要开发新的方法来鉴定新的受体调节剂。在这项提案中，使用我们使用跨膜ORF收集的新型高通量筛选，我们将识别阳离子亲离子神经递质受体的功能调节器。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，这种公正的、全基因组的、灵敏的筛查方法将对许多研究领域产生深远的影响。

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.