Vanier Scholar researching role of ankyrin-B in heart cell development

PhD student Nicole York (Swayne and Arbour Labs; pictured) has received the prestigious Vanier Canada Graduate Scholarship for 2023 from the Canadian Institute of Health Research. Vanier Scholars are considered Canada’s top graduate students and are awarded $50,000 annually for up to three years.

Nicole is investigating the role of ankyrin-B (ANKB), a scaffolding protein, in the development of heart muscle cells called cardiomyocytes. This work may provide insight to how a variant of the protein called ANKB p.S646F could contribute to structural heart disease and electrical disturbance, which are associated with the variant in the Gitxsan First Nation community.

The presence of ANKB p.S646F was first identified in the community while long QT syndrome was being investigated through a long-standing research partnership with the Gitxsan. Sudden cardiac death and structural heart problems, such as heart defects at birth and weakened heart muscle in later years, have been observed to be associated with the variant.

“My thesis research stems from a larger community-based project [based in the Swayne and Arbour Labs] that aims to design preventative and evidence-based medicine interventions,” she says. “Improved understanding of ANKB’s role in heart cell development will provide insight into the impact of ANKB in disease, while investigating ANKB p.S646F will contribute knowledge on the variant’s impacts within this community.”

Nicole predicts that ANKB – which acts as an anchor or scaffold for ion channels – regulates the structure of mature cardiomyocytes by directing the proper placement of ion channels and transporters in the cell membrane during a process called cellular differentiation. This process, through which immature cardiomyoblasts become mature cardiomyocytes, involves highly complex and coordinated changes in protein levels and cellular shape that go hand-in-hand with changes in cellular excitability. Nicole suspects that ANKB is required early on in cellular differentiation to organize its interacting partners, which leads to proper cell morphology and function.

“Given that ANKB interacts with channels and structural components in cells, ANKB likely regulates both cellular structure and function,” she says.

It is important to investigate how the ANKB p.S646F variant could change the differentiation process and ultimately the structure and function of mature cardiomyocytes. These changes could contribute to the phenotypes observed in affected individuals.

To investigate the role of ANKB and potential impact of the ANKB p.S646F variant, Nicole is determining the profile of ANKB expression by measuring transcript (RT-qPCR) and protein (western blotting) levels of differentiation markers, ANKB, and ANKB-interacting proteins across cardiomyocyte cell differentiation. She is also altering the expression of ANKB – via up and downregulation, as well as ANKB variant expression – to determine the effects on cell development.

Nicole will be able to observe how changes in ANKB affect the cell structure of cardiomyocytes using Dr. Swayne’s Leica SP8 confocal and super-resolution (stimulated emission depletion, or STED) microscope. She will also use confocal/STED microscopy and immunoprecipitation to confirm novel ANKB protein interactions. She will map the interaction site and use cell-penetrating peptides based on these sequences to block these interactions and determine the impact on cardiomyocyte development.

Alongside this work, Nicole will be directing experiments investigating the functional impacts of ANKB disruption by imaging calcium dynamics with live confocal microscopy. This work will be done in collaboration with lab manager Joel Rivera and directed studies undergraduate student K’sana Wood Lynes-Ford.