The ASPIRE Path in Molecular Medicine

As a Postdoctoral Fellow at Vanderbilt, under the direction of Charles Sanders, my research focus has been to explain the interplay between membrane protein flexibility and structure that lead to robust function and dysfunction involved in human disease, with a special emphasis on ion channels involved in the heart contraction cycle. Given the high estimated frequency of ion channel mutation carriers, the driving force of this type of project is not only to provide a reliable estimate of if a variant is pathogenic, but also if a variant is not pathogenic. My main project to date in the Sanders laboratory is the interaction of the single span membrane protein KCNE3 with the potassium channel KCNQ1 and the modulation of the complex by estrogen. KCNE3 binds to KCNQ1 to induce both constitutive (voltage-independent) channel activation and enhanced conductance in epithelial chloride secretion. Our work generated a set of precise models that offer an explanation of how KCNE3 locks KCNQ1 into its activated state ultimately leading to a structure-based mechanism of how this complex is modulated by the presence of estrogen. Importantly, I was able to propose mutating a critical residue at the interaction site between the two proteins, an experiment that resulted in complete abrogation of the channel complex estrogen sensitivity. This project suggests the feasibility of applying structural biology to the task of assessing phenotypic effects of rare variants on important proteins.

Prince J. Kannankeril, M.D., M.S.C.I. Associate Professor of Pediatrics is my clinical mentor. Dr. Kannankeril’s interests are in electophysiologic studies (heart rhythm abnormalities), specifically, the genetic basis of arrhythmias in pediatrics and congenital heart disease. Shadowing Dr. Kannankeril has exposed me to the concerns of patients, and family members of patients, that have a genetic variant of unknown significance but have presented with some arrhythmia, syncope, or torsades de pointes. The greatest concern for patients and parents of patients is what is their risk for some severe cardiac event and how much do they need to change their lifestyle to bring this risk to an acceptable range.