Excellence in Research: Developing Molecular Probes to Study the Brain

点击翻译按钮获取中文摘要

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.