Lorena Ceballos Gonzalez
Research Mentor: Adam Helms
Mentor Department: Internal Medicine / Cardiovascular Medicine, Medicine
Author(s): Lorena Ceballos Gonzalez, Ahmed Elmansi, Sabrina Friedline, Yao-Chang Tsan, Eric Smith, Adam Helms
Session: Session 1 (9:00 AM – 9:50 AM)
Presentation Type: Poster 92
Abstract
Arrhythmogenic ventricular cardiomyopathy (ARVC) is a heart muscle disease causing detachment in cell-to-cell junctions. As a result, myocytes die and are replaced with scar tissue. This cardiomyopathy is typically caused by genetically determined abnormalities of cardiac desmosomes. This research focuses on abnormal desmosomal proteins caused by mutations in the gene desmoplakin (DSP). The epidermal growth factor signaling pathway (EGFR) activates key downstream pathways critical for regulating cell growth, division and differentiation. Inhibition of EGFR signaling has been shown to improve assembly of desmosomal proteins. The inhibition of EGFR signaling through the use of Erlotinib, a drug mostly used in cancer treatment, has been shown in other ARVC models to increase cardiomyocyte cohesion. Using human pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) organized in micron-scale muscle bundles on two-dimensional elastomer substrates, the effectiveness of Erlotinib will be evaluated in increasing cardiomyocyte cohesion and preventing adhesion failure. Preliminary results show that treating cardiomyocytes with reduced desmoplakin expression improves cardiomyocyte cohesion and reduces adhesion failure. To understand the mechanisms behind the protective effect of Erlotinib, an RNA sequencing and proteomics experiment using mass spectrometry will be performed to observe the downstream effects of EGFR inhibition. By understanding the mechanisms underlying the beneficial effect of Erlotinib on cardiomyocyte cohesion, there is a possibility to more effectively and uniquely target individual downstream pathways for future treatments of DSP ARVC. Additionally the improvement in cardiomyocyte cohesion in cells treated with Erlotinib highlights the inhibition of EGFR as a possible treatment for arrhythmogenic cardiomyopathy.
