Alpha6* nAChRs in Dopamine Transmission and Nicotine Dependence

Alpha6* nAChR 在多巴胺传递和尼古丁依赖性中的作用

• 批准号: 8028952
• 负责人: Ryan Michael Drenan
• 金额: $ 9万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-17 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8028952
• 关键词: Address; Adolescent; Adult; Agonist; Animals; Area; Behavior; Behavioral; Biogenesis; Biological; Biology; Birth; Brain; California; Cells; Cellular Neurobiology; Cellular biology; Cholinergic Receptors; Chronic; Communities; Community Healthcare; Corpus striatum structure; Data; Data Set; Development; Disease; Dopamine; Drug Delivery Systems; Electrophysiology (science); Environment; Event; Exhibits; Faculty; Future; Goals; Growth; Health Services Research; Image; Imagery; Implant; Institutes; Institution; Knock-in Mouse; Knowledge; Label; Laboratories; Learning; Life; Measures; Mediating; Mediator of activation protein; Mentors; Methods; Microscopy; Midbrain structure; Mood Disorders; Mus; Neuraxis; Neurons; Neurosciences; Neurotransmitter Receptor; Neurotransmitters; Nicotine; Nicotine Dependence; Nicotinic Receptors; Occupations; Paper; Parkinson Disease; Pattern; Pharmacotherapy; Phase; Phenotype; Photons; Physiological; Physiology; Positioning Attribute; Predisposition; Presynaptic Receptors; Presynaptic Terminals; Proteins; Public Health; Publishing; Regulation; Research; Research Personnel; Research Training; Resources; Role; Running; Schizophrenia; Scientist; Secure; Slice; Smoke; Smoker; Techniques; Technology; Testing; Training; Transgenic Mice; Universities; abstracting; cholinergic; design; dopamine system; dopaminergic neuron; drug reinforcement; early adolescence; gain of function; graduate student; multi-photon; mutant; neuronal cell body; neurotransmitter release; novel; osmotic minipump; phase 1 study; postsynaptic; presynaptic; programs; receptor; receptor expression; relating to nervous system; research study; selective expression; smoking cessation; stoichiometry; success; trafficking; transmission process

DESCRIPTION (provided by applicant): My immediate goals are to continue my research and training in electrophysiology, biological imaging and neuroscience. During the K99 phase (2 years), I will conduct experiments and be trained in electrochemical recording methods and multi-photon imaging. I will publish papers and search for a job as an independent faculty/investigator during the K99 phase, and will transition to the R00 independent phase (3 years) upon securing a faculty position. The total duration of the project is 5 years. Environment: the K99 phase of this project will be conducted at the California Institute of Technology, which affords an excellent research and learning environment for postdoctoral scientists. Caltech has a strong neuroscience community, excellent faculty, and many highly productive and resourceful postdoctoral scholars and graduate students for one to collaborate with. Caltech also runs the Biological Imaging Center through the Beckman Institute, a resource that will be a very important part of my training plan. For the institution where I will conduct my R00 phase studies, I will choose an institute or university with excellent neuroscience resources and faculty that will put me in the best position for growth and success. Research: this research program is designed to test the hypothesis that specific nicotinic ACh receptors are important for modulating release of neurotransmitters such as dopamine. In particular, I will test the idea that nicotinic receptors containing 16 subunits, which are found on dopamine presynaptic terminals, are important mediators of dopamine release. I will also test the idea that the ability of these receptors to mediate dopamine release is governed by their subcellular regulation by the neurons where they reside. Finally, I will test the idea that 16 receptor expression and function are significantly altered when animals are exposed to chronic nicotine. Thus, these experiments will determine whether these receptors are important in dopamine release and in disorders such as nicotine dependence. To carry out these experiments, I designed and built a set of novel transgenic mouse lines to particularly isolate aspects of 16 nAChR biology. For example, some experiments will utilize mice with hypersensitive 16 receptors that amplify and isolate 16 physiology and behavior, while other experiments will make use of mice expressing fluorescently-labeled 16 receptors that allow for direct visualization of these proteins in live neurons. PUBLIC HEALTH RELEVANCE: This project is designed to give the research and health care community a better understanding of particular neurotransmitter receptors that may be important in neural disorders such as nicotine dependence, Parkinson's disease, affective disorders, or schizophrenia. The knowledge that will be produced by this research may be useful in designing and testing better drug therapies for these or other related disorders.

描述（由申请人提供）：我的近期目标是继续我在电生理学，生物成像和神经科学方面的研究和培训。在K99阶段（2年），我将进行实验，并接受电化学记录方法和多光子成像的培训。在K99阶段，我将发表论文并寻找一份独立教师/调查员的工作，并在获得教师职位后过渡到R00独立阶段（3年）。项目总工期为5年。环境：本项目的K99阶段将在加州理工学院进行，为博士后科学家提供了良好的研究和学习环境。加州理工学院有一个强大的神经科学社区，优秀的师资队伍，以及许多生产力高、足智多谋的博士后学者和研究生。加州理工学院还通过贝克曼研究所运营生物成像中心，这将是我培训计划中非常重要的一部分。对于我将进行R00阶段研究的机构，我会选择一个拥有优秀神经科学资源和师资的机构或大学，这将使我处于最好的成长和成功的位置。研究：该研究项目旨在测试特定的尼古丁乙酰胆碱受体对调节多巴胺等神经递质的释放很重要的假设。特别是，我将测试含有16个亚基的尼古丁受体是多巴胺释放的重要介质的想法，这些亚基位于多巴胺突触前末端。我还将测试这些受体调节多巴胺释放的能力是由它们所在神经元的亚细胞调节所控制的。最后，我将测试当动物暴露于慢性尼古丁时，16受体的表达和功能显着改变的想法。因此，这些实验将确定这些受体在多巴胺释放和尼古丁依赖等疾病中是否重要。为了进行这些实验，我设计并构建了一套新的转基因小鼠系，以特别分离16种nAChR生物学的各个方面。例如，一些实验将利用具有超敏受体的小鼠来放大和分离生理和行为，而其他实验将利用表达荧光标记受体的小鼠来直接观察活神经元中的这些蛋白质。