Excellence in Research: Developing Molecular Probes to Study the Brain

在化学系生命过程化学（CLP）项目的支持下，温斯顿-塞勒姆州立大学的吉尔·基思教授正在研究设计化学探针的发展，这些探针有可能产生有关分子结构如何影响大脑受体区域识别的信息，这是理解基本神经化学信号事件的关键，最终是某些人类行为。该项目依赖于使用计算方法来设计，然后化学制造具有研究这些重要信号事件所需属性的探针，这是通过使用设计的分子作为成像探针来设想的。探针的物理位置将由其与化学受体选择性相互作用的独特化学信号提供。这个项目的成功完成有可能提供成像探针，用于进一步了解与学习和记忆有关的神经化学途径。受NSF BRAIN计划的启发，这个跨学科的合作研究项目将专注于基础化学方法，这些方法有可能帮助解开大脑的复杂性，同时也将培养下一代神经化学家，其中许多人来自代表性不足的群体。由于在Keith小组中进行研究的大多数学生都是非裔美国女性，因此该项目的完成将增加接受训练进行神经化学严格基础研究的女性和少数族裔的数量，从而增强多元化的劳动力，同时保持全球竞争力。进一步扩大该项目的影响是，它的重点是向高中生和本科生展示团队科学在多学科环境中的重要性，并让他们与来自代表性不足的人群的K-12青少年一起进行动手实验，以鼓励他们追求科学事业。该项目的最终目标是合成选择性化学探针，这些探针可能是多巴胺能和大麻素受体/转运体正电子发射断层扫描（PET）研究的重要候选者。混合方法将用于确定要合成和评价的化合物。据推测，操纵二苯基甲氧基哌啶的芳香环和/或氮基，即二苯基吡啶（DPP），将产生选择性结合多巴胺转运体（DAT）或大麻素-1受体（CB1R）的化合物。将在Keith教授的实验室中进行二苯基pyraline （DPP）类似物的合成、纯化、表征和生物学测试。将对这些探针进行生物学测试，以确定DPP类似物与DAT和/或CB1结合的能力；还将确定DAT和CB1的选择性。将对探针进行额外的评估，并使用“通过-不通过”标准的迭代方法来确定PET探针开发的最佳候选物。重要的是，与该项目相关的活动将加强与维克森林医学院（WFSM）教师的现有合作伙伴关系，该学院与温斯顿-塞勒姆州立大学（WSSU）教师合作，在研究实验室和课堂环境中培训WSSU学生，并通过科学出版物和演讲传播他们的工作。这种伙伴关系预计将增加继续获得博士学位的学生人数，并建立在过去从WFSM和其他机构获得高级学位的WSSU学生的成功基础上。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemistry of Life Processes (CLP) Program in the Division of Chemistry, Professor Jill Keith of Winston-Salem State University is studying the development of designed chemical probes that have the potential to yield information about how their molecular structure impacts their recognition by receptor regions in the brain, which are key to understanding fundamental neurochemical signaling events, and eventually certain human behaviors. This project relies upon the use of computational methods to design and then chemically make probes with the needed properties for studying these important signaling events, which is envisioned by using the designed molecules as imaging probes. The physical location of the probes will be provided by their unique chemical signal upon their selective interaction with chemical receptors. Successful completion of this project has the potential to offer imaging probes that may be used to further understand neurochemical pathways linked to learning and memory. Taking a cue from the NSF BRAIN Initiative, this interdisciplinary, collaborative research project will focus on fundamental chemistry approaches that have the potential to help unravel the brain’s complexity, while also training the next generation of neurochemists, many of whom are individuals from underrepresented groups. As most students who perform research in the Keith group are African American women, completion of this project will increase the number of women and minorities who are trained to perform rigorous fundamental research in neurochemistry, thereby enhancing a diversified workforce while sustaining global competitiveness. Further broadening the impacts of the project is its focus on showing high school and undergraduate students the importance of team science in a multidisciplinary setting, as well as engaging them in hands-on experiments with K-12 youth from underrepresented populations in an effort to encourage them to pursue a science career. The ultimate goal of this project is to synthesize selective chemical probes that may be important candidates for positron emission tomography (PET) studies of dopaminergic and cannabinoid receptors/transporters. A hybrid approach will be used to determine the compounds to be synthesized and evaluated. It is hypothesized that manipulating the aromatic rings and/or nitrogen group of the diphenylmethoxypiperidine, that is diphenylpyraline (DPP), will yield compounds that selectively bind the dopamine transporter (DAT) or cannabinoid-1 receptor (CB1R). The synthesis, purification, characterization, and biological testing of diphenylpyraline (DPP) analogs using procedures in Professor Keith's laboratories will be conducted. Biological testing of these probes will be performed to determine DPP analogs’ ability to bind to the DAT and/or CB1; the DAT and CB1 selectivities will also be determined. Additional assessment of the probes will be conducted, and an iterative approach with "go - no go" criteria will be used to identify the best candidates for PET probe development. Importantly, activities associated with this project will strengthen the existing partnership with Wake Forest School of Medicine (WFSM) faculty who collaborate with Winston-Salem State University (WSSU) faculty to train WSSU students in research lab and classroom settings, as well as disseminate their work through scientific publications and presentations. This partnership is anticipated to grow the number of student participants who go on to receive their PhD and is built upon past successes of students from WSSU who received their advanced degrees from WFSM and other institutions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.