Program: Molecular Cell Biology
Current advisor: Colin G. Nichols, PhD
Undergraduate university: St. Johns University Minnesota
Cantú Syndrome (CS) is characterized by a cascade of cardiovascular features, including cardiomegaly, cardiac hypercontractility, systemic hypotension, and vascular dilation and tortuosity. CS is caused by gain-of-function (GoF) mutations in genes that encode subunits of cardiovascular ATP-sensitive potassium (KATP) channels: KCNJ8 (Kir6.1) and ABCC9 (SUR2). Most studies have focused on KATP activity within the heart, but it has recently become clear that the cardiovascular features of CS – including those affecting the heart – are driven primarily by KATP GoF within the vasculature. Generally, the aim of my current project is to understand how vascular electrophysiology is impacted by CS mutations, and how these electrical changes within the vasculature may give rise to and/or protect against cardiovascular disease. To do so, I am using patch-clamp electrophysiology to study vascular smooth muscle cells (VSMCs) that are acutely dissociated from CRISPR-Cas9-engineered CS mice. I have also generated a human vascular cell model for CS by obtaining patient-derived human induced pluripotent stem cells (hiPSCs), and then differentiating these cells into hiPSC-VSMCs. By functionally characterizing the ion channel activity of these cells, I hope to provide a novel understanding of ‘normal’ hiPSC-VSMC electrophysiology and compare it to primary VSMC electrophysiology, and to understand how CS-related electrical abnormalities in human cells compares to those observed in primary mouse cells, which will provide insight to whether altered vascular electrophysiology arises via cell-autonomous mechanisms.
Zhang H, Hanson A, de Almeida TS, Emfinger C, McClenaghan C, Harter T, Yan Z, Cooper PE, Brown GS, Arakel EC, Mecham RP, Kovacs A, Halabi CM, Schwappach B, Remedi MS, Nichols CG. 2021 Complex consequences of Cantu syndrome SUR2 variant R1154Q in genetically modified mice. JCI Insight, 6(5):e145934.
McClenaghan C, Hanson A, Lee SJ, Nichols CG. 2020 Coronavirus Proteins as Ion Channels: Current and Potential Research. Front Immunol, 11():573339.
McClenaghan C, Hanson A, Sala-Rabanal M, Roessler HI, Josifova D, Grange DK, van Haaften G, Nichols CG. 2018 Cantu syndrome-associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms. J Biol Chem, 293(6):2041-2052.