Our research program is focused on pharmacogenomics and disease modeling. Applying a combination of hiPSC culture, tissue engineering, sequencing, high-throughput assays, and drug screens, we can establish the genetic cause of a patient's specific drug response.
Our major interest is modeling cancer therapy-induced cardiomyopathy and heart failure using hiPSC-derived cardiomyocytes, endothelial cells, and fibroblasts. This method allows us to recapitulate a patient's off-target cardiotoxic response to drugs such as anthracyclines, tyrosine kinase inhibitors, and monoclonal antibodies. Major mechanisms we study include transporters, drug metabolism, mitochondrial behavior, reactive oxygen species, DNA-damage, calcium handling, and sarcomeric damage.
Cardiac regenerative medicine
We are looking at hiPSC-derived and directly reprogrammed cells in cardiac cell therapy and the fundamental questions of how we can improve the yield, engraftment, survival, and function of these cells. This work involves the study of immunogenicity, in vivo differentiation, methods for direct reprogramming, and the induction of in vivo cell type-specific proliferation using small molecules.
We are interested in modeling patient-specific drug toxicity in many lineages in addition to hiPSC-derived cardiomyocytes, studying drug metabolism using hiPSC-derived hepatocytes, and modeling cancer treatment-induced infertility using hiPSC-derived primordial germ cells (PGCs) and follicles.
hiPSC are unique as a model for cancer as they offer homogeneous unlimited expansion without the phenotypic drifts seen with patient-derived xenograft (PDX) models and without the inability to model early stage cancer seen with immortalized cell lines. We are using these cells in a reductionist approach to model the underlying mechanisms of tumorigenesis, germline influence on drug response, and drug resistance.
Cardiomyopathy and heart failure
hiPSC-derived cardiomyocytes are a unique tool for cardiomyopathy and hypertrophy phenotype screening. Currently, we are researching novel drugs that inhibit and/or reverse these phenotypes in a variant-specific manner.
Pluripotent stem cell biology
We are actively researching how modifying the pluripotent state can influence subsequent differentiation, synthetic matrices, the maintenance of proliferative differentiation intermediates, and direct reprogramming. We are working on increasingly refined, simplified, and reproducible methods for producing cells of the cardiovascular (cardiomyocytes, endothelial cells, fibroblasts, and smooth muscle), hematopoietic (megakaryocytes), hepatic (hepatocytes), renal (proximal tubular and podocyte cells), neural (sensory and motor neurons), and reproductive (PGCs/follicles) lineages. Once cells are differentiated to a specific lineage, we work to control subtype specification and maturation.
Genomics and bioinformatics
The ability to capture a single human genome in culture as a hiPSC and then differentiate it to any desired cell type holds enormous potential to interrogate the genome. We are interested in how gene expression analysis (RNA-seq) of drug treated hiPSC-derived cells can be combined with whole genome association studies (WGAS) to provide expression quantitative trait loci (eQTL). As part of this effort, we are working on numerous tools to enhance whole-genome analysis, such as supercomputing and developing streamlined pipelines.
As part of our stem cell effort, we are working on expanding the scale and throughput of differentiation, using methods such as bioreactors and suspension culture. We are also working on the construction of multicellular organ-on-a-chip systems to better develop the most accurate cellular models to recapitulate the patient's original drug response.
CRISPR-based knockout screening
To functionally validate how SNPs influence drug response, we are performing CRISPR-based ATG knockouts, AAVS1-based overexpression, and SNP corrections. We are also performing LentiCRISPR-based high-throughput drug screens to discover new drugs that can alter this response.
We have our own mini drug discovery facility, and we use a variety of tools for drug testing, including Labcyte Echo liquid handling, automated triple-mode plate readers, a Vala Sciences Kinetic Image Cytometer for high-throughput calcium and high-content imaging, and a Nanion Syncropatch for automated patch clamp.