Description:

Please join the Department of Pharmacology for a Works-in-Progress presentation by Lisa Wren and Tarek Mohamed, Ph.D.

Lisa Wren - DGP/MSCI Graduate Student in Alfred L. George's Laboratory

"Understanding Calmodulinopathies in Cellular and Animal Models"

Sudden cardiac death (SCD) affects nearly 400,000 people each year, making it the largest cause of natural death in the United States. Approximately 1,000-5,000 of SCD cases occur in children and young adults under the age of 35 and tragically shorten the expected life-years of affected individuals. Mutations found in one of three distinct genes (CALM1, CALM2, or CALM3) encoding an identical calcium sensing protein, calmodulin (CaM), are associated with very severe ventricular arrhythmia phenotypes that potentiate the risk of SCD in the young. Therefore, the purpose of this study is to mechanistically understand CaM mutant arrhythmogenicity and to elucidate potential modifiers that influence the development of arrhythmogenic phenotypes in cellular and animal models. The variable phenotypes associated with the recurrent CaM N98S mutation drove us to engineer mouse lines with this mutation in either Calm1 or Calm2 using genome editing. These unique mouse lines now enable us to determine the influence of sex, age, and genetic background on arrhythmogenic phenotypes and establish mouse models that can be used to investigate disease pathogenesis and test new therapies.

Tarek Mohamed, Ph.D. - Postdoc in Paul Burridge's Laboratory

"SLC28A3 Genetic Polymorphisms in Doxorubicin-induced Cardiotoxicity"

The clinical utility of the anthracycline doxorubicin is limited by its dose-dependent cardiotoxicity1. It is currently not possible to predict which patients will be affected or to protect patients who will likely suffer this devastating side effect. Recently, SNP (rs7853758 G>A, L461L) in SLC28A3 was found to be associated with lower risk of doxorubicin-induced cardiotoxicity (DIC) in three different independent cohorts2,3. Although this finding presents a potential advance in applying pharmacogenomics approach to cardio-oncology, further functional validation for this SNP and linked SNPs/haplotypes is required to provide a robust connection between SLC28A3 polymorphisms and DIC especially given the mixed track record of transitioning GWAS data into clinical practice. In this work, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) model will be used a platform for studying the validity and mechanisms of SLC28A3 genetic polymorphisms in regulating DIC.