Career Development Award

描述(由申请者提供)：这是给Annette Fleckenstein博士的职业发展奖建议。她是犹他大学的药理学和毒理学教授。她从事药物滥用研究已有13年，在阐明精神刺激剂对多巴胺(DA)转运体(DAT)和囊泡单胺转运体-2(MAT-2)调节和功能的影响方面做出了重要贡献，特别是与苯丙胺的神经毒性作用有关。申请者是目前的K02获奖者，这使得申请者可以极大地减少她的机构责任，并将75%的时间投入到她的申请中所描述的研究和专业发展上。现要求续签该奖项，以便申请人能够继续指导检验假设的研究，这些研究假设：1)甲基苯丙胺(Meth)诱导的DAT复合体的形成与兴奋剂引起的多巴胺能缺陷有关，并且可能促成；2)哌甲酯独特地影响单胺能囊泡的功能和分布，其机制包括VMAT-2M介导的DA转运动力学的新变化；以及3)与细胞内DA管理有关的“后期事件”对于冰毒造成的持续性多巴胺能缺陷至关重要，并且这些事件在青春期大鼠和发育期间接受冰毒治疗的大鼠中都不存在。对这项K02奖项的持续支持不仅将允许申请人在这些研究上进行扩展，还将为她的实验室开发新技术方面的专业知识。特别是，K02的资金将促进将自我给药技术整合到她的实验室中，这将允许调查转运蛋白在临床相关范例中是否发生了变化。此外，K02的续期将允许申请者继续并扩大与犹他大学内外的研究人员的跨学科合作努力，如提案中所述。公共卫生相关性：精神刺激性药物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裁决的支持将提供支持，使申请人能够研究甲基苯丙胺、可卡因和哌醋甲酯等兴奋剂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.