- Tarek's Paper on RARG Published in Cell Stem Cell09/15/2021
RARG variant predictive of doxorubicin-induced cardiotoxicity identifies a cardioprotective therapy
Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but its use is limited by dose-dependent cardiotoxicity. A recent genome-wide association study identified a SNP (rs2229774) in retinoic acid receptor-γ (RARG) as statistically associated with increased risk of anthracycline-induced cardiotoxicity. Here, we show that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with rs2229774 and who suffered doxorubicin-induced cardiotoxicity (DIC) are more sensitive to doxorubicin. We determine that the mechanism of this RARG variant effect is mediated via suppression of topoisomerase 2β (TOP2B) expression and activation of the cardioprotective extracellular regulated kinase (ERK) pathway. We use patient-specific hiPSC-CMs as a drug discovery platform, determining that the RARG agonist CD1530 attenuates DIC, and we confirm this cardioprotective effect in an established in vivo mouse model of DIC. This study provides a rationale for clinical prechemotherapy genetic screening for rs2229774 and a foundation for the clinical use of RARG agonist treatment to protect cancer patients from DIC.
- New Postdoctoral Fellow Positions Available09/09/2021
Postdoctoral Fellow Positions Available
Two postdoctoral fellow positions are available in the laboratory of Dr. Paul Burridge in the Department of Pharmacology and the Center for Pharmacogenomics at Northwestern University Feinberg School of Medicine, Chicago, IL.
Successful candidates will be involved in projects involving:
- hiPSC-derived cardiomyocytes and endothelial cells to model the genomic basis of chemotherapy-induced toxicity
- hiPSC-derived cardiomyocytes to model the genomic basis of arrhythmias and sudden cardiac death.
- Cardiac organoid models of cardiac structural disease
- Development of very large-scale iPSC differentiation
- Skeletal muscle and adipose differentiation
- Cardiac regenerative medicine (cardiac engraftment and direct reprogramming)
includes:iPSC reprogramming, iPSC culture, differentiation methodologies, CRISPR, bioreactors, hiPSCdisease modeling, bioinformatics, genomics, eQTL, GWAS, drug response assays, chemotherapy drug response/toxicity mechanisms.
Good verbal and written communication skills in English are essential. The successful candidate will join a dynamic research environment in the Department of Pharmacology, which offers both basic science and clinical translational opportunities to explore fundamental questions in pharmacogenomics. More details can be found here: http://labs.feinberg.northwestern.edu/burridge/
Starting salary will be according to NIH (NRSA) scale and commensurate with experience.
Please send a CV (including publications), a cover letter containing a brief description of research experience and interests, and a list of 2-3 references
Northwestern University is an Equal Opportunity, Affirmative Action Employer of all protected classes, including veterans and individuals with disabilities. Women and minorities are encouraged to apply. Hiring is contingent upon eligibility to work in the United States.
The positions will remain open until filled.
- Burridge Lab Awarded Second R0109/01/2021The Burridge lab has been awarded a second R01. In this grant, funded by the National Cancer Institute, we will study the genomics of anthracycline cardiotoxicity in African American children in collaboration with St. Jude Children's Research Hospital in Memphis.
- Postdocs awarded grants08/30/2021Postdoctoral Fellows Tarek Magdy and Davi Lyra-Leite have been awards American Heart Association Grants. Tarek won a three-year Career Development Award and Davi won a Postdoctoral Fellowship, congratulations to both!
- Tarek's Review "Use of hiPSC to Explicate Genomic Predisposition to anthracycline-Induced Cardiotoxicity" Published01/15/2021
Use of hiPSC to Explicate Genomic Predisposition to Anthracycline-Induced Cardiotoxicity
The anticancer agents of the anthracycline family are commonly associated with the potential to cause severe toxicity to the heart. To solve the question of why particular a patient is predisposed to anthracycline-induced cardiotoxicity (AIC), researchers have conducted numerous pharmacogenomic studies and identified more than 60 loci associated with AIC. To date, none of these identified loci have been developed into US FDA-approved biomarkers for use in routine clinical practice. With advances in the application of human-induced pluripotent stem cell-derived cardiomyocytes, sequencing technologies and genomic editing techniques, variants associated with AIC can now be validated in a human model. Here, we provide a comprehensive overview of known genetic variants associated with AIC from the perspective of how human-induced pluripotent stem cell-derived cardiomyocytes can be used to help better explain the genomic predilection to AIC.