Imbalances in neurotransmitter levels are known to cause myriad psychiatric and neurological disorders, such as schizophrenia, depression, and Parkinson?s disease. Therefore, the ability to quantify neurotransmitter storage and release in vivo in mice, in a noninvasive way, would yield information important to the study of disease, including new molecular mechanisms; a goal I share with NIMH. I have a unique opportunity at Columbia working with my primary mentor Dr. David Sulzer, a leading researcher in the cell biology and physiology of neurotransmitter release. I will combine my backgrounds in chemistry and neuroscience in order to translate the fluorescent false neurotransmitter strategy, which has yielded many new insights into the behavior of dopamine synapses, into magnetic resonance spectroscopy probes. With additional training in 19F- MRS, I plan to develop several Magnetic resonance False Neurotransmitters (MFNs) over the course of the K99 and R00 phases. The MFN strategy uses fluorine-containing, pH sensitive probes, that accumulate in synaptic vesicles alongside their targeted neurotransmitter. Because of their pH-sensitivity, MFNs will have a different chemical shift in acidic synaptic vesicles than when in the pH-neutral cytoplasm or extracellular milieu. In this way, we can quantify how much MFN is in synaptic vesicles as a means of assessing the health of that neurotransmitter system, and we can also quantify MFN release by measuring the intensity changes in the acidic- and neutral-pH chemical shift peaks. In the mentored K99 phase, I aim to characterize a dopamine MFN that I have previously characterized in vitro and ex vivo, in response to chemical dopaminergic challenges including amphetamine, as well as in different populations of mice with transgenic mutations to their capacity to store monoamine neurotransmitters. In the independent R00 phase, I aim to expand the MFN strategy to develop probes for norepinephrine and serotonin. To accomplish these aims, I will pursue two more years of postdoctoral training in MRS under the supervision and direction of my mentors, all of which are located at Columbia. Dr. Sulzer will remain my primary mentor. I will receive hands-on training from Dr. Jia Guo and Dr. Larry Kegeles, experts in MRS. During the two years of my mentored K99 phase, they will help me become proficient in MRS. I will receive additional advice and career mentorship from Dr. Dalibor Sames, a chemist with extensive experience in developing false neurotransmitters, and Dr. Gary Miller, an expert in synaptic vesicle function. Along with Dr. Sulzer, Drs. Sames and Miller will form a career advisory committee to help me develop as an independent researcher. At Columbia, I will have all the necessary guidance, tools, and resources to be sufficiently trained and successfully complete this project. With these new skills, I will successfully transition an academic faculty position as an independent investigator.
Imbalances in neurotransmitter levels are known to cause myriad psychiatric and neurological disorders, such as schizophrenia, depression, and Parkinson?s disease. Magnetic Resonance False Neurotransmitters (MFNs) offer a means of quantifying levels of neurotransmitter in vivo that would help build a better understanding and molecular basis for these diseases. I aim to develop and characterize MFNs for dopamine, norepinephrine, and serotonin, with the ultimate goal of using them in humans to better study, diagnose, and treat disease.
