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Dissertation Defense: The Voltage Gated Sodium Channel β1/β1B Subunits: Emerging Therapeutic Targets in the Heart

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Zachary Williams

Dissertation Defense: The Voltage Gated Sodium Channel β1/β1B Subunits: Emerging Therapeutic Targets in the Heart

Zachary Williams

Graduate Student, Translational Biology, Medicine, and Health
Graduate Research Assistant, Gourdie Lab, Fralin Biomedical Research Institute at VTC
Dec. 4, 2023 at 10 a.m.
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About this Dissertation

Voltage-gated sodium channels are composed of pore-forming α-subunits, and modulatory and multifunctional associated β subunits. While much of the field of cardiac electrophysiology and pathology has focused on treating and preventing cardiac arrhythmias by targeting the α subunit, there is also evidence that targeting the β subunits, particularly SCN1B, the gene that encodes β1 and an alternatively spliced variant β1B, has therapeutic potential. The first attempt at targeting the β1 subunit was with the generation of and treatment with an SCN1B Ig domain mimetic peptide βadp1. Here Williams, mentored by Robert Gourdie, describes further investigation into the function and mode-of-action of both βadp1 and novel peptides derived from the original βadp1 sequence. The researchers find that in a heterologous expression system βadp1 initially disrupts β1-mediated trans-homophilic adhesion, but after approximately 30 hours eventually increases adhesion. Novel mimetic dimers increase β1 adhesion up to 48 hours post-treatment. Furthermore, it appears that βadp1 may increase β1 adhesion by upregulating the intramembrane proteolysis of β1, a process which has important downstream implications and effects on translation. Despite these exciting findings, the team was unable to translate them into a primary culture of cardiac cells with endogenous expression of β1 because we found that both neonatal rat cardiomyocytes and isolated adult mouse cardiomyocytes do not express β1 at detectable levels, whereas they do appear to express β1B. In summary, the research shows exciting findings on the function and mode-of-action of SCN1B mimetic peptides and their therapeutic potential in targeting the β1 subunit, but further work is needed to determine the translatability of the lab's findings to in vivo models and eventually to humans.

More About the Candidate and Project

Education

Virginia Tech, Translational Biology, Medicine, and Health, Ph.D. Candidate

Sterling College, B.S., Chemistry and Mathematics

Training

Graduate Research Assistant, Gourdie Lab, Fralin Biomedical Research Institute at VTC

Mentor

Robert Gourdie, Ph.D., Commonwealth Research Commercialization Fund Eminent Scholar in Heart Reparative Medicine Research and Director, Center for Vascular and Heart Research, Fralin Biomedical Research Institute at VTC

Committee Members

Publications

Marsh SR, Williams ZJ, Pridham KJ, Gourdie RG. Peptidic Connexin43 Therapeutics in Cardiac Reparative Medicine. J Cardiovasc Dev Dis. 2021 May 5;8(5):52. doi: 10.3390/jcdd8050052. Erratum in: J Cardiovasc Dev Dis. 2022 Apr 16;9(4): PMID: 34063001; PMCID: PMC8147937.

Teng ACT, Gu L, Di Paola M, Lakin R, Williams ZJ, Au A, Chen W, Callaghan NI, Zadeh FH, Zhou YQ, Fatah M, Chatterjee D, Jourdan LJ, Liu J, Simmons CA, Kislinger T, Yip CM, Backx PH, Gourdie RG, Hamilton RM, Gramolini AO. Tmem65 is critical for the structure and function of the intercalated discs in mouse hearts. Nat Commun. 2022 Oct 18;13(1):6166. doi: 10.1038/s41467-022-33303-y. PMID: 36257954; PMCID: PMC9579145.

Williams ZJ, Alvarez-Laviada A, Hoagland D, Jourdan LJ, Poelzing S, Gorelik J, Gourdie RG. Development and Characterization of the Mode-of-Action of Inhibitory and Agonist Peptides Targeting the Voltage-Gated Sodium Channel SCN1B/β1 Subunit In process


Presentations

Williams, Z.J., et al., Effects of Voltage Gated Sodium Channel β subunit mimetic peptide βadp1. Presented at the Fralin Biomedical Research Institute Annual Retreat, 2023

Williams, Z.J., et al., Effects of Voltage Gated Sodium Channel β subunit mimetic peptides on SCN1B/β1. Presented at Research in Progress Seminar Series, Fralin Biomedical Research Institute at Virginia Tech, 2023

Williams, Z., et al., Abstract 11526: Voltage Gated Sodium Channel β1 Subunit Mimetic Peptide PS2L Increases Regulated Intramembrane Proteolysis of SCN1B/β1. Circulation, 2022. 146(Suppl_1): p. A11526-A11526. (American Heart Association Scientific Sessions Moderated Digital Poster 2022)

Williams, Z.J., et al., Abstract P1092: Voltage Gated Sodium Channel Subunit Mimetic Peptide βadp1 Increases Regulated Intramembrane Proteolysis Of Scn1b/β1. Circulation Research, 2022. 131(Suppl_1): p. AP1092-AP1092. (American Heart Association BCVS sessions Poster 2022)

  • Winner, Translational Biology, Medicine and Health Health Science and Technology Hokie Pitch, 2019
  • Ruth L. Kirschstein F31 Predoctoral Individual National Research Service Award, 2021
  • 3rd place poster award, 2nd annual Fralin Biomedical Research Institute Center for Vascular and Heart Research Symposium, 2023
  • Translational Biology, Medicine, and Health Graduate Program Mentor, 2021-2022
  • Flip the Fair participant, 2022
  • Commercialization Mentor/Lecturer, 2020-present