Northwestern University Feinberg School of Medicine

Paul Burridge Lab

News

Read the latest news from the Burridge Lab. The links below take you to articles where you can learn more about our lab’s latest achievements, awards, and honors.

News

  • We're Hiring Postdocs and Research Technicians
    04/21/2022

    Two postdoctoral fellow positions and a research technician II position 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)

    Desirable expertise includes: iPSC reprogramming, iPSC culture, differentiation methodologies, CRISPR, bioreactors, hiPSC disease 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/

    Reseach Technician II position should apply via NU: https://careers.northwestern.edu Job ID: 44378

    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 to:  paul.burridge@northwestern.edu

    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. 

     

  • Tarek's Paper on Inhibiting SLC Transporters Published in Circulation
    12/08/2021

    Background: Multiple pharmacogenomic studies have identified the synonymous genomic variant rs7853758 (G>A, L461L) and the intronic variant rs885004 in SLC28A3 as statistically associated with a lower incidence of anthracycline-induced cardiotoxicity (AIC). However, the true causal variant(s), the cardioprotective mechanism of this locus, the role of SLC28A3and other solute carrier (SLC) transporters in AIC, and the suitability of SLC transporters as targets for cardioprotective drugs has not been investigated.

    Methods: Six well-phenotyped, doxorubicin-treated pediatric patients from the original association study cohort were re-recruited and human induced pluripotent stem cell-derived cardiomyocytes were generated. Patient-specific doxorubicin-induced cardiotoxicity (DIC) was then characterized using assays of cell viability, activated caspase 3/7, and doxorubicin uptake. The role of SLC28A3 in DIC was then queried using overexpression and knockout of SLC28A3 in isogenic hiPSCs using a CRISPR/Cas9. Fine−mapping of the SLC28A3 locus was then completed after SLC28A3 resequencing and an extended in silico haplotype and functional analysis. Genome editing of potential causal variant was done using cytosine base editor. SLC28A3−AS1 overexpression was done using a lentiviral plasmid-based transduction and was validated using stranded RNA-Seq after ribosomal RNA depletion. Drug screening was done using the Prestwick drug library (n = 1200) followed by in vivo validation in mice. The effect of desipramine on DOX cytotoxicity was also investigated in eight cancer cell lines.

    Results: Here, using the most commonly used anthracycline, doxorubicin, we demonstrate that patient-derived cardiomyocytes recapitulate the cardioprotective effect of the SLC28A3 locus and that SLC28A3 expression influences the severity of DIC. Using Nanopore¬-based fine-mapping and base editing we identify a novel cardioprotective SNP rs11140490 in the SLC28A3 locus which exerts its effect by regulating an antisense long noncoding-RNA (SLC28A3-AS1) that overlaps with SLC28A3. Using high-throughput drug screening in patient-derived cardiomyocytes and whole organism validation in mice, we identify the SLC competitive inhibitor desipramine as protective against DIC.

    Conclusions: This work demonstrates the power of the human induced pluripotent stem cell model to take a SNP from a statistical association through to drug discovery, providing human cell-tested data for clinical trials to attenuate DIC.

  • Tarek's Paper on RARG Published in Cell Stem Cell
    09/15/2021

    RARG variant predictive of doxorubicin-induced cardiotoxicity identifies a cardioprotective therapy

    PDF

    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 Available
    09/09/2021

    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)

    Desirable expertise includes: iPSC reprogramming, iPSC culture, differentiation methodologies, CRISPR, bioreactors, hiPSC disease 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 to:  paul.burridge@northwestern.edu

    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 R01
    09/01/2021
    The 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.