Regulation of alpha7 nAChRs and NACHO

α7 nAChR 和 NACHO 的调节

• 批准号: 10392780
• 负责人: SUSAN L TSUNODA
• 金额: $ 7.13万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392780
• 关键词: Acetylcholine; Affect; Alzheimer' s Disease; Attention; Brain; Cell membrane; Cells; Client; Complex; Development; Disease; Drosophila genus; Endoplasmic Reticulum; Epilepsy; Event; Functional disorder; Future; Gatekeeping; Goals; Golgi Apparatus; Homeostasis; Human; Learning; Mammals; Mediating; Memory; Mental Depression; Microscopy; Molecular; Molecular Chaperones; Molecular Genetics; Motor Activity; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Pathologic; Pathology; Pathway interactions; Physiological Processes; Play; Proteins; Publishing; Receptor Signaling; Receptor Up-Regulation; Regulation; Role; Schizophrenia; Seizures; Signal Transduction; Study models; Surface; Synapses; Synaptic plasticity; System; Testing; Therapeutic; Time; Up-Regulation; alpha-bungarotoxin receptor; cholinergic; genetic approach; in vivo; insight; mutant; nervous system disorder; neuropsychiatry; overexpression; receptor; recruit; relating to nervous system; response; targeted treatment; trafficking

Tsunoda, Susan Project Summary Nicotinic acetylcholine receptors (nAChRs) are involved in a wide range of physiological processes, from motor activity to complex brain functions, including learning/memory function and attention. nAChRs have also been shown to mediate homeostatic synaptic plasticity (HSP), a protective mechanism stabilizing neural activity. As such, dysfunction or loss of nAChRs has been implicated in a variety of neurological diseases. For example, the α7 nAChR has been implicated in Alzheimer’s Disease, nicotine addiction, nicotine-induced seizures, as well as schizophrenia. Indeed, enhancing nAChR signaling is a long-validated approach to treating multiple neuropsychiatric/pathological disorders. Despite this importance, much remains to be understood about how nAChRs are assembled and trafficked to the plasma membrane in neurons, especially when neurons encounter changes in activity. The proposed studies focus on NACHO, a newly identified endoplasmic reticulum (ER)- resident protein, shown to be a client-specific chaperone of nAChRs, and essential for trafficking α7 nAChRs. We use molecular-genetic approaches in Drosophila to overcome some of the limitations of studying intracellular α7 nAChRs in mammalian neurons. We: 1) examine the temporal relationship of NACHO and α7 nAChR up- regulation during HSP, 2) test whether NACHO and α7 depend on one another during HSP and whether one is sufficient to up-regulate the other, and 3) examine how the localization of α7 and NACHO in the ER/Gogli changes during HSP.

角田，苏珊 项目概要 烟碱乙酰胆碱受体 (nAChR) 参与广泛的生理过程，从 运动活动对复杂的大脑功能（包括学习/记忆功能和注意力）也有影响。 已被证明可以介导稳态突触可塑性（HSP），这是一种稳定神经活动的保护机制。 因此，nAChR 的功能障碍或缺失与多种神经系统疾病有关。 α7 nAChR 也与阿尔茨海默病、尼古丁成瘾、尼古丁诱发的癫痫发作有关 事实上，增强 nAChR 信号传导是一种经过长期验证的治疗多种疾病的方法。 尽管神经精神/病理学疾病很重要，但关于其如何发生仍有许多问题需要了解。 nAChR 在神经元中组装并运输到质膜，特别是当神经元遇到 拟议的研究重点是 NACHO，一种新发现的内质网 (ER)。 常驻蛋白，被证明是 nAChR 的客户特异性伴侣，对于运输 α7 nAChR 至关重要。 我们在果蝇中使用分子遗传学方法来克服研究细胞内的一些局限性 哺乳动物神经元中的 α7 nAChR：1）检查 NACHO 和 α7 nAChR 上行的时间关系。 HSP 期间的调节，2) 测试 NACHO 和 α7 在 HSP 期间是否相互依赖以及其中之一是否相互依赖 足以上调另一个，3) 检查 α7 和 NACHO 在 ER/Gogli 中的定位如何 HSP 期间的变化。