Molecular regulation of nicotinic acetylcholine receptors

 描述(申请人提供)：在美国，与吸烟有关的疾病每年导致超过40万人过早死亡1，但仍有数千人在与戒烟作斗争。尼古丁是烟草中的主要成瘾成分，它与特定类型的烟碱型乙酰胆碱受体(NAChRs)相互作用，改变受体的功能状态和细胞表面的表达。虽然nAChRs在尼古丁成瘾中的作用已得到很好的证实，但这些受体在正常大脑功能和尼古丁暴露后的生物调节机制尚不清楚。在这个提案中，我将使用模型系统秀丽线虫来研究神经细胞表面nAChRs的动力学。[在目标1中，我将定义在GABA能运动神经元树突上表达的nAChRs的亚单位组成。其次，我将研究免疫球蛋白结构域蛋白OIG-1在尼古丁受体聚集中的作用。]最后，在第三个目标中，我将研究如何 神经元活动和尼古丁暴露影响nAChRs的动态和亚细胞分布。这些研究将解决有关nAChRs生物学的基本问题，并为我提供遗传学、显微镜和电生理学技术方面的强大培训，这些技术将是我继续科学发展的基本工具。

 DESCRIPTION (provided by applicant): Smoking-related diseases result in more than 400,000 premature deaths in the United States each year1, yet thousands struggle with smoking cessation. Nicotine, the major addictive component in tobacco, interacts with specific classes of nicotinic acetylcholine receptors (nAChRs), altering the functional state of the receptors and expression at the cell surface. Although the role of nAChRs in nicotine addiction has been well established, mechanisms for the biological regulation of these receptors during normal brain function and following nicotine exposure are poorly defined. In this proposal, I will use the model system C. elegans to investigate the dynamics of nAChRs on the neuronal cell surface. [In Aim 1, I will define the subunit composition of nAChRs expressed on the dendrites of GABAergic motor neurons. Secondly, I will investigate the role of OIG-1, an immunoglobulin domain protein, in nicotinic receptor clustering.] Finally, in the third Aim I will investigate how neuronal activity and nicotine exposure shape the dynamics and subcellular distribution of nAChRs. These studies will address fundamental questions about the biology of nAChRs and provide me with strong training in genetics, microscopy, and electrophysiology techniques that will be essential tools in my continuing scientific development.