Aim 1: To identify which SLC transporters are responsible for doxorubicin uptake in to cardiomyocytes. (a) Directed approach: Use CRISPR/Cas9 to knockout combinations of a 14 of SLC transporters in hiPSC that are 1, highly expressed in hiPSC-CMs and 2, have previously been associated with anthracycline transport via GWAS/CGAS and/or have a published association with anthracycline transport. (b) Unbiased approach: Use an arrayed lentiCRISPR library to knockout all SLC genes individually in hiPSC-CMs. (c) Combine positive hits from both studies and generate multi-SLC knockout hiPSC lines with zero or minimal doxorubicin uptake in to cardiomyocytes. In each case we will assess doxorubicin uptake using our established high-throughput flow cytometry-based assay and a plate-base viability assay. Aim 2: Repurpose and discover drugs that specifically attenuate doxorubicin transport via SLCs in to cardiomyocytes but not cancer cells (a) Assess existing drugs known to inhibit SLC function for effect on doxorubicin accumulation in cardiomyocytes and breast cancer cells. (b) Use a cheminfomatics approach to map the common targets between identified SLCs and drugs that inhibit them. Use this information to design novel drugs that specifically affect these SLCs expressed in cardiomyocytes and not cancer cells.
|Effective start/end date
|1/1/19 → 12/31/19
- Northwestern Memorial Hospital (Letter 02/22/19)
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