Our lab investigates genetic differences in drug response and toxicity and searches for new therapeutic approaches targeting ABC transporters.
In the UC San Francisco lab of Deanna Kroetz, PhD, research projects fall into these broad groups:
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.
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
The UCSF School of Pharmacy is an ideal place for pharmacogenomics research. The Kroetz Lab is part of the Department of Bioengineering and Therapeutic Sciences, which was the center of the Pharmacogenetics of Membrane Transporters (PMT) project in the NIH Pharmacogenomics Research Network (PGRN) from 2000-2015. The PMT project seeded diverse efforts in pharmacogenomics at UCSF that remain a focus of the department. The UCSF Helen Diller Family Cancer Center is also a member of the Alliance for Clinical Trials in Oncology, a group which has been critical for the large-scale clinical pharmacogenomic studies in the Kroetz Lab. Collaborations among members of the UCSF Institute for Human Genetics and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research provide a rich environment for these pharmacogenetic studies. All these reasons speak to the exclusive focus on excellence in health science and health care at UCSF, as well as its intensely collaborative nature.
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.
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
The Department of Bioengineering and Therapeutic Sciences at the UCSF School of Pharmacy offers a stimulating research setting for molecular pharmacology studies. Identification of new drug targets drives investigations in both basic science departments in the School, and colleagues in the Department of Pharmaceutical Chemistry and Biochemistry have expertise in structural and chemical biology, which provides a rich intellectual environment for these studies. Our studies are also complementary to ongoing efforts in the UCSF Helen Diller Family Cancer Center to design precision therapeutics.
Deanna Kroetz directs the lab and is a molecular and clinical pharmacologist. She has a background and training in pharmacokinetics, drug metabolism, and drug transport, and she has a deep understanding of interindividual variation in drug response and toxicity. Her focus on translational research is reflected in the breadth of her research, spanning clinical pharmacogenetic association studies, functional genomics studies in cells and model organisms, and animal- and cell-based molecular pharmacology studies. Kroetz was elected a fellow of the American Association of Pharmaceutical Scientists (AAPS) in 2008 and the American Association for the Advancement of Science (AAAS) in 2018. She is Deputy Editor-in-Chief of Clinical and Translational Science.
Members of the Kroetz Lab have broad expertise in human genetics, molecular and clinical pharmacology, cellular models of drug response and membrane transporter biochemistry. This breadth provides a rich training ground for students and postdoctoral scholars, and the opportunity for cross-cultivation of ideas across two distinct research programs. Dr. Kroetz Is committed to training the next generation of scientists and has received mentoring awards from the Northern California Association for Women in Science, the American Society for Clinical Pharmacology and Therapeutics and the American College of Clinical Pharmacology.