Colin Clark, M5G
|
MSTP Learning Community: Bean MSTP Entry Date: June 13, 2016 |
|
PhD Program: Molecular Physiology & Biophysics |
Mentor: Chris Ahern, PhD |
| Graduate Profile | Lab Website |
Acute Chemical Silencing of Voltage Gated Sodium Channels in Physiological Context
The cardiac sodium channel NaV1.5 is essential for fast depolarization and impulse conduction in the heart. Inherited mutations in the NaV1.5 channel cause Long QT Syndrome, Brugada Syndrome, and Dilated Cardiomyopathies. Current heterologous cellular platforms used to study NaV1.5 mutations lack the physiological context required to fully appreciate the molecular and cellular basis of disease phenotypes. Further, transgenic and KO models of these channelopathies are resource intensive and limited in assessing the mechanisms of NaV1.5 function and regulation. Our goal is to validate a broadly applicable mouse model which provides improved precision for the study of NaV1.5 within the native cardiomyocyte milieu. Toward this goal, we have created a drug sensitive chimeric NaV1.5/1.7 channel which is silenced by aryl- and acyl- sulfonamide drugs, termed “GX” drugs. We have confirmed that this chimeric channel, referred to as NaV1.5-GX, is biophysically indistinguishable from the WT NaV1.5 channel, and is sensitive to two GX compounds that we have synthesized. NaV1.5-GX will replace the wildtype NaV1.5 in a B6 mouse line, allowing the native channel to be reversibly silenced in vitro and in vivo. We envision using this unique resource to explore the mechanisms underlying the function of NaV1.5 in health and disease. We intend to clarify the controversial role of non-NaV1.5 isoforms in the heart, assess putative NaV functional dimerism, and to study individual NaV1.5 channelopathies. Overall, we expect this strategy to provide access to new questions in cardiac electrophysiology, produce data with greater mechanistic relevance than current models, and serve as proof of principle for applying this approach in other NaV isoforms.
Committees:
2017-2018 - APSA Midwest Regional Meeting Planning Committee
Awards:
2016 - Excellence in Pediatric Basic Science Research, Medical Student Research Day, Sept 9
2017 - Excellence in Translational Neuroscience Research, Medical Student Research Day, Sept 15
Education:
2015 - BA, Molecular, Cellular & Developmental Biology - University of Colorado
Publications:
Minard AY, Clark CJ, Ahern CA, & Piper RC (2023). Beta-subunit-eliminatd eHAP expression (beHAPe) cells reveal subunit regulation of the cardiac voltage-gated sodium channel. Journal of Biological Chemistry, 105132.
Galles GD, Infield DT, Clark CJ, Hemshorn ML, Manikandan S, Fazan F,...& Ahern CA (2023). Tuning phenylalanine fluorination to assess aromatic contributions to protein function and stability in cells. Nature Communications, 14(1), 59.