Chronic drug exposures; serial MRI studies

描述(由申请人提供)： 这个计划的目的是提供受保护的时间，让我能够投入75%以上的精力继续进行3个相互关联的项目。我是一名新独立的NIDA R01(DA 14674)首席研究员，使用功能磁共振成像(FMRI)来阐明可卡因急性脑效应中性别差异的潜在机制。我是NIDA R01(DA11231，PI：M.Pollack)分包合同的联合首席研究员，使用磷光谱(31P MRS)研究美沙酮维持阿片类药物依赖受试者的大脑代谢。我是一项私人基金会拨款的首席研究员，将非人类灵长类动物慢性可卡因自我给药模型与磁共振(MR)技术结合起来，研究长期接触可卡因对大脑结构和功能的影响。在K01大奖期间，我通过研究可卡因和哌醋甲酯对大脑的急性影响，积累了临床磁共振成像方面的专业知识。我发现了脑血管对可卡因反应的性别差异，这可能是慢性可卡因对大脑影响的性别差异的基础。这项工作直接导致了我的R01拨款。我还参与了对慢性可卡因、海洛因和多药滥用者的研究，这些研究导致了上面提到的分包合同，并第一手了解了人体模型的混淆和局限性。这促使我寻求合作并开发资金，以使用非人类灵长类动物模型对受控的慢性药物暴露进行前瞻性的MRI、MRS和fMRI研究。我在猴子研究中的主要目标是确定自我注射可卡因的累积剂量与脑功能障碍严重程度(根据人类研究的建议)之间的关系，并确定急性药物效应如何导致慢性药物引起的脑功能障碍。这项工作是与维克森林大学的琳达·波里诺博士合作进行的。K02奖将允许我稳定和灵活地继续在这些相互关联的项目上工作。这种稳定性尤其重要，因为我应用在与维克森林合作中学到的专业知识来开发方法和资金，以便在McLean医院4.0特斯拉扫描仪和拟议的9.4特斯拉扫描仪上进行猴子高场磁共振研究。K02提供的受保护的时间将使我有更多的时间培训和指导对进行这些类型的跨学科研究感兴趣的下一代科学家，并将帮助我从新独立的研究员过渡到独立的研究员。

DESCRIPTION (provided by applicant): The aim of this program is to provide protected time to allow me to devote more than 75% of my effort to continue work on 3 interrelated projects. I am a newly independent Principal Investigator on a NIDA R01 (DA 14674) using functional MRI (fMRI) to elucidate mechanisms underlying sex differences in cocaine's acute brain effects. I am a co-Principal Investigator on a subcontract to a NIDA R01 (DA11231, PI: M. Pollack) using phosphorus spectroscopy (31p MRS) to study cerebral metabolism in methadone-maintained opiate dependent subjects. I am a Principal Investigator on a private foundation grant combining a nonhuman primate chronic cocaine self-administration model along with magnetic resonance (MR) technology to study brain structural and functional effects of chronic cocaine exposures. I developed expertise in clinical MR imaging during a K01 award by conducting studies of the acute brain effects of cocaine and methylphenidate. I identified sex differences in cerebrovascular reactivity to cocaine that may be bases for sex differences in chronic cocaine's brain effects. That work led directly to my R01 grant. I also collaborated on studies of chronic cocaine, heroin, and polydrug abusers that led to the subcontract noted above and learned first hand about confounds and limitations of human models. This led me to pursue collaborations and develop funding to conduct prospective MRI, MRS, and fMRI studies of controlled chronic drug exposures using non-human primate models. My primary goals in monkey studies are to identify relationships between cumulative self-administered cocaine dose and brain dysfunction severity (as suggested by human studies) and to determine how acute drug effects lead to chronic drug-induced brain dysfunction. This work is in collaboration with Dr. Linda Porrino at Wake Forest University. The K02 award will allow me stability and flexibility to continue work on these interrelated projects. This stability is particularly important as I apply expertise learned in my Wake Forest collaboration to develop methods and funding to conduct monkey high field MR studies on the McLean Hospital 4.0 Tesla scanner and on a proposed 9.4 Tesla scanner. The protected time offered by the K02 will allow me more time to train and mentor the next generation of scientists interested in conducting these types of interdisciplinary research, and will assist me in making the transition from newly independent to independent investigator.