Biography: My academic and research background has positioned me perfectly to pursue therapeutic development for neurological diseases. I completed my undergraduate work at Northwestern University, focusing on a comprehensive science curriculum, studying not only biology, but incorporating chemistry, physics, mathematics, and computational science. I supplemented this coursework with two major research pursuits - engineering polymer nanoparticles for high-sensitivity DNA detection and then endogenous siRNAs in the brains of D. melanogaster using both traditional biochemical methods and more novel bioinformatics. The University of Michigan Medical Scientist Training Program then provided me with an opportunity to use my background knowledge to address clinically and scientifically important problems. My research in graduate school under Dr. Jason Gestwicki involved utilizing both chemical and biochemical approaches to understand the role of heat shock proteins in promoting and maintaining the cancer phenotype. This work also involved initial steps in drug development. Upon returning to medical school, I quickly became struck by the devastating effect that neurological diseases had on many aspects of a patient’s life. I found myself further impressed by our limits in treating many of these degenerative conditions, disproportionately so when compared to many other medical specialties and therefore pursued a clinical residency in Neurology at the University of Michigan. During residency, I was exposed to a wide breadth of neurological diseases, including movement disorders. My clinical work with Drs. Vikram Shakkottai and Henry Paulson alerted me to the incredible need for an improved understanding of movement disorders, and a particular opportunity to help our ataxia patients. Currently, I am completing a multi-disciplinary fellowship in movement disorders. While a large portion of my time is dedicated to seeing patients with an emphasis on hereditary ataxias, I have supplemented this with basic science research in stem cell and genetic technologies under Dr. Vikram Khurana (BWH) as well as clinical trial design and pharmaceutical development with Praxis Precision Medicines, a biotech company based in Boston. Upon returning to the University of Michigan as a Clinical Instructor, I intend to draw upon my diverse, yet in-depth, background to further pursue novel therapeutics for degenerative ataxias.
Project Title: “Discovery and development of potassium channel activators for therapeutic rescue in Spinocerebellar Ataxias”.
Project Description: The Spinocerebellar Ataxias (SCAs) are a class of dominantly inherited degenerative disorders causing progressive decline in balance, speech, and gait, often resulting in wheelchair confinement. Currently, no treatment exists for the SCAs, and there is substantial need to improve motor function and slow neurodegeneration. A major hallmark of SCAs is cerebellar Purkinje Cell (PC) degeneration. In SCA mouse models, alterations in PC spiking due to ion channel dysfunction occur concurrently with motor impairment and well before cell loss. Reduced expression and activity of large-conductance calcium-activated potassium (BK) channels underlie these changes in PC membrane excitability in several SCAs. Our group has previously showed that restoring BK channel expression or function rescued membrane hyperexcitability, improved motor dysfunction, and reduced PC degeneration. Therefore, improving BK activity presents an attractive therapeutic strategy in SCA1 and other SCAs.
Traditional ion channel analysis has relied on manual patch clamp, a highly specific but low throughput technique. Using a novel automated patch clamp (APC) instrument at the University of Michigan, we designed a high throughput screen (HTS) to identify BK channel agonists. Primary hits were taken for concentration response curves (CRCs) and followed up in manual cerebellar slice recording. After extensive efforts, only one compound (BK-20) survived this validation process, limiting structure-activity-relationship (SAR) studies. The next phase of this work will thus focus on 1) expanding our primary screen, which was limited by the COVID-19 pandemic, to increase the number of chemical scaffolds available for SAR analysis and 2) initial pharmacokinetic (PK) studies along with behavioral assays in an SCA1 mouse model.
While the long-term goal of this work is to develop therapeutics for SCAs, the objective of this specific project is to generate multiple chemical scaffolds that activate BK and to initialize pre-clinical studies as a proof of concept for future drug development. My central hypothesis is that ion channel dysfunction plays a central role in propagating disease pathology in SCAs and that restoration of BK activity will improve motor dysfunction and delay cellular degeneration.
Project Mentors: Henry Paulson, M.D., Ph.D. (primary mentor, UM) and Vikram Shakkottai, M.D., Ph,D. (co-mentor, UTSW)