Our lab investigates genetic differences in drug response and toxicity and searches for new therapeutic approaches targeting ABC transporters.
Pharmacogenomics
Genetic differences are a key determinant of whether individuals receive the intended therapeutic effect and whether they develop adverse effects when administered standard doses of a drug. Identification of genetic variants that predict drug response or toxicity is critical for realizing the benefits of precision medicine. However, identifying these variants and understanding how they affect drug response in humans is challenging. Our lab is addressing this using clinical studies in humans and laboratory studies in cells and model organisms.
Why now
Advances in genotyping and DNA sequencing technologies have revolutionized the field of human genetics, allowing us to easily get a picture of DNA sequence variation across the entire genome. Genome-wide genotyping arrays coupled with imputation that uses publicly available exome and whole genome sequence data from diverse populations can provide a comprehensive picture of genetic variation in an individual. These genotype data can then be used to discover associations with clinical phenotypes that reflect drug response and toxicity. Advances in high-throughput cellular assays for function of noncoding regions in DNA, induced pluripotent stem cell models of drug response and the application of the genome-editing CRISPR-Cas9 technology allows us to functionally characterize the effect of genetic variation in both coding and noncoding regions of the genome. Our lab is working to:
- Discover genetic variation in the human genome that leads to observable phenotypes (traits) relevant to drug therapy
- Understand at the molecular level the relationships between changes in DNA sequence and drug response
ABC Transporter Pharmacology
The ATP-binding cassette (ABC) superfamily of transmembrane transporters play critical roles in the efflux of endogenous molecules and xenobiotics from cells. Their ability to efflux drugs from cells has been associated with multidrug resistance in cancer and protection of critical tissues like the brain, testis and fetus from exposure to toxins. These same transporters also facilitate the movement of endogenous compounds across cell membranes and have been implicated in multiple diseases. The function of ABC transporters in the efflux of both xenobiotics and endogenous molecules make them attractive drug targets. However, effective targeting of the ABC transporters remains challenging. Our lab is addressing this using structural biology and studies in cells and animals.
Why now
In recent years, new roles have emerged for the function of ABC transporters in regulating the levels of endogenous signaling molecules. Human genetic association studies and investigations in animal models have linked variation in ABC transporter function with both normal physiologic processes and pathophysiologic changes underlying disease. This supports the therapeutic targeting of ABC transporter function for not only preventing drug resistance but also for treatment of human disease. Advances in cryo-EM are rapidly expanding our understanding of the molecular structures of membrane proteins, which will be critical for designing selective and potent inhibitors of the ABC transporters. Our lab is:
- Solving the molecular structure of the ABC transporter MRP4 to understand the transport mechanism and to design inhibitors
- Evaluating the role of MRP4 in tumor immunosensitivity