Career Development Award

描述（由申请人提供）：这是安妮特·弗莱肯斯坦博士的职业发展奖提案。她是犹他大学药理学和毒理学教授。她活跃于药物滥用研究13年，在阐明精神兴奋剂对多巴胺（DA）转运体（DAT）和囊泡单胺转运体-2 （\/MAT-2）的调节和功能的影响，特别是与安非他明的神经毒性作用有关的影响方面做出了重要贡献。申请人目前是K02获得者，这使得申请人可以大大减少她的机构责任，并将75%的时间用于研究和专业发展，如她在申请中所述。请求更新该奖项，以便申请人可以继续指导研究，以测试以下假设：1)甲基苯丙胺（METH）诱导的DAT复合物形成与兴奋剂引起的多巴胺能缺陷有关，并可能导致多巴胺能缺陷；2)哌醋甲酯通过一种包括vmat - 2m介导的DA转运动力学的新转变的机制独特地影响单胺能囊泡功能和分布；3)与细胞内DA管理相关的“后期事件”对于甲基安非他明引起的持续多巴胺能缺陷至关重要，这些事件在青春期大鼠和发育期间服用甲基安非他明的大鼠中都不存在。继续支持该K02奖不仅可以让申请人扩展这些研究，还可以发展其实验室新技术的专业知识。特别是，K02的资助将有助于将自我给药技术纳入她的实验室，这将允许调查转运蛋白是否在临床相关范例中发生改变。此外，K02的续期将允许申请人继续和扩大与犹他大学内外的研究人员的跨学科合作努力。公共卫生相关性：精神兴奋剂滥用是一个重大的公共卫生问题。囊泡单胺转运体-2和多巴胺转运体是这些药物的主要靶点。因此，对K02奖的支持将支持申请人研究兴奋剂如甲基苯丙胺、可卡因和哌醋甲酯对转运蛋白功能的影响。

DESCRIPTION (provided by applicant): This is a Career Development Award proposal for Dr. Annette Fleckenstein. She is a Professor of Pharmacology and Toxicology at the University of Utah. She has been active in drug abuse research for 13 years and has made important contributions to elucidating the effects of psychostimulants on dopamine (DA) transporter (DAT) and vesicular monoamine transporter-2 (\/MAT-2) regulation and function, especially as related to the neurotoxic effects of the amphetamines. The applicant is a current K02 recipient, and this has permitted the applicant to dramatically decrease her institutional responsibilities and devote 75% of her time to research and professional development as described in her application. Renewal of this award is requested so that the applicant can continue directing research which test the hypotheses that: 1) methamphetamine (METH)-induced DAT complex formation is associated with, and may contribute to, the dopaminergic deficits caused by the stimulant; 2) methylphenidate uniquely affects monoaminergic vesicular function and distribution by a mechanism that includes novel shifts in VMAT-2M-mediated DA transport kinetics; and 3) "latter-stage events" related to intracellular DA management are critical for the persistent dopaminergic deficits caused by METH, and that these events are absent in both adolescent rats and those treated with METH during development. Continued support of this K02 award will not only allow the applicant to expand upon these studies, but also develop expertise in technologies new to her laboratory. In particular, funding of the K02 will facilitate the incorporation of self-administration technology into her laboratory that will permit investigation as to whether transporters are altered in that clinically relevant paradigm. Further, renewal of the K02 will allow the applicant to continue and expand interdisciplinary collaborative efforts with researchers both within and outside of the University of Utah as delineated in the proposal. PUBLIC HEALTH RELEVANCE: Psychostimulant abuse is a significant public health issue. The vesicular monoamine transporter-2 and the dopamine transporter are principal targets of these agents. Accordingly, support for this K02 award will provide support to allow the applicant to study the impact of stimulants such as methamphetamine, cocaine and methylphenidate on transporter function.