Alpha6* nAChRs in Dopamine Transmission and Nicotine Dependence

职位描述(申请人提供)：我目前的目标是继续在电生理学、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方面的培训。我将在K99阶段发表论文并寻找一份独立教员/研究员的工作，并在获得教员职位后过渡到R00独立阶段(3年)。项目总工期为5年。环境：该项目的K99阶段将在加州理工学院进行，该学院为博士后科学家提供了良好的研究和学习环境。加州理工学院拥有强大的神经科学社区，优秀的教师，以及许多高生产率和足智多谋的博士后学者和研究生可以合作。加州理工学院还通过贝克曼研究所运营生物成像中心，这一资源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，我会选择一所拥有优秀神经科学资源和教师的学院或大学，这将使我处于成长和成功的最佳位置。研究：这项研究计划旨在检验特定的尼古丁ACh受体对调节多巴胺等神经递质释放的重要性这一假设。特别是，我将测试包含16个亚基的尼古丁受体是多巴胺释放的重要媒介的想法，这些亚基位于多巴胺突触前终末。我还将测试这样一种观点，即这些受体介导多巴胺释放的能力是由它们所在神经元的亚细胞调控决定的。最后，我将测试当动物长期接触尼古丁时，16受体的表达和功能会发生显著变化的想法。因此，这些实验将确定这些受体是否在多巴胺释放和尼古丁依赖等疾病中起重要作用。为了进行这些实验，我设计并建立了一组新的转基因小鼠系，以特别分离16个nAChR生物学的方面。例如，一些实验将利用带有超敏16受体的小鼠来放大和分离16的生理和行为，而另一些实验将利用表达荧光标记的16受体的小鼠，从而允许在活神经元中直接显示这些蛋白质。 公共卫生相关性：该项目旨在让研究和医疗保健团体更好地了解特定的神经递质受体，这些受体可能在尼古丁依赖、帕金森病、情感障碍或精神分裂症等神经疾病中发挥重要作用。这项研究将产生的知识可能有助于设计和测试针对这些或其他相关疾病的更好的药物疗法。

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.