Neurobehavioral Analysis of Norepinephrine Transporter Variants

描述（由申请人提供）：候选人的研究记录表明致力于生物医学研究的职业生涯，特别是了解儿茶酚胺（CA）系统生理学的调节及其在神经精神疾病中的作用。兰迪布莱克利，作为本申请的导师，有着出色的研究记录，并指导了许多博士后研究员成功的职业生涯作为独立的调查。在指导委员会的指导下，其成员是Ariel Deutch，Danny Winder和大卫罗伯逊，他们都是儿茶酚胺系统生理学和疾病过程的专家，我们已经将我们认为对候选人的科学发展至关重要的组件纳入了该应用程序。该申请将在原代去甲肾上腺素能神经元培养和基因改变小鼠中去甲肾上腺素转运蛋白遗传变异体的转基因表达领域提供新的培训，包括使用免疫荧光显微镜，运输测定和行为分析来了解去甲肾上腺素转运蛋白遗传变异体的影响。根据职业发展计划，候选人将参加课程和研讨会，接受教学培训，并已安排担任范德比尔特几门课程的讲师。范德比尔特大学提供了一个上级环境来开展这项活动，包括转基因小鼠生产，小鼠行为分析和共聚焦显微镜的核心设施。该申请提出了目前在布莱克利实验室中未应用于去甲肾上腺素转运蛋白研究的方法，从而提供了一些新颖且独立的研究途径。候选人成功的出版记录，各种奖项和奖学金的认可，以及通过会议，课堂教学或实验室学习和教授他人的持续动力，表现出作为独立科学家的繁荣，承诺和成功潜力。 相关性：去甲肾上腺素（NE）转运蛋白（NET）是NE失活的介质，通过NE再摄取进入细胞，并可能在心血管功能，注意力，记忆和情绪障碍中发挥作用。NET基因序列的变异，导致NET蛋白质的改变，已在人类中被确定。选定的遗传变异将在细胞中表达，用于活动，并在小鼠中表达与记忆和注意力相关的心血管功能和行为。了解NET变异体的功能将有助于我们了解NET内的遗传变异如何影响人类复杂的性状和疾病

DESCRIPTION (provided by applicant): The candidate's research record demonstrates a commitment to a career in biomedical research and, specifically, to understand the regulation of catecholamine (CA) systems physiology and their role in neuropsychiatric disease. Randy Blakely, serving as mentor of this application, has an outstanding research record and has mentored numerous postdoctoral fellows to successful careers as independent investigators. With the guidance of a mentoring committee, whose members are Ariel Deutch, Danny Winder and David Robertson, all experts in catecholamine system physiology and disease processes, we have incorporated into this application the components we deem critical to the candidate's scientific development. The application will provide novel training in the area of transgene expression of norepinephrine transporter genetic variants in primary noradrenergic neuronal culture and genetically altered mice, including use of immunofluorescence microscopy, transport assays and behavioral analyses to understand the impact of norepinephrine transporter genetic variants. Under the career development plan the candidate will participate in courses and seminars to receive didactic training and has also arranged to serve as instructor in several Vanderbilt courses. Vanderbilt University offers a superior environment to conduct the activities under this award, including core facilities for transgenic mouse production, mouse behavioral analysis and confocal microscopy. This application proposes approaches not presently applied in the Blakely laboratory to the study of the norepinephrine transporter, thus providing some novel and independent avenues of research. The candidate's successful publication record, recognition by various awards and fellowships and continued drive to learn and teach others through conferences, classroom teaching, or in the laboratory, demonstrate an exuberance, commitment and potential for success as an independent scientist. Relevance: The norepinephrine (NE) transporter (NET), is a mediator of NE inactivation by reuptake of NE into cells and may play a role in disorders of cardiovascular function, attention, memory and mood. Variation in NET genetic sequence, leading to altered NET protein, has been identified in humans. Selected genetic variants will be expressed in cells for activity and in mice for cardiovascular function and behaviors linked to memory and attention. Understanding the function of NET variants will contribute to our understanding of how genetic variation within NET contributes to human complex traits and disease