Our lab investigates genetic differences in drug response and searches for new drug targets to treat kidney disease.
In the UC San Francisco lab of Deanna Kroetz, PhD, research projects fall into these broad groups:
Genetic differences are increasingly recognized as 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 personalized 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
- Lab studies in cells and model organisms
Advances in genotyping and DNA sequencing technologies have revolutionized the field of human genetics, allowing us to quickly get a picture of variation in DNA sequence across the entire genome. Genome-wide genotyping arrays coupled with imputation that uses publically available information on exome and whole genome sequences from ethnically diverse populations allow us to get 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 and the application of the new genome-editing CRISPR-Cas9 technology also 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 has been the center of the Pharmacogenetics of Membrane Transporters (PMT) project in the NIH Pharmacogenomics Research Network (PGRN) since 2000. 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 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.
Arachidonic acid is a 20-carbon long-chain polyunsaturated fatty acid that is a precursor of numerous bioactive molecules collectively referred to as eicosanoids. Cytochrome P450 (P450) eicosanoids have been implicated in vascular reactivity, inflammation, and response to cellular injury. There is a growing interest in therapeutic approaches to modulation of in vivo levels of P450 eicosanoids for treatment of cardiovascular and renal disease. Our lab is:
- Testing small molecules that can manipulate eicosanoid levels for treatment of these diseases
- Working to understand the role of P450 eicosanoids in the kidney’s response to acute and chronic injury
The burden of renal disease is increasing in Western populations (in part due to the increasing incidence of diabetes), and there are currently no effective therapeutic strategies for prevention or treatment. P450 eicosanoids have only recently been shown by our research and others’ to have beneficial effects in animal models of renal injury, providing the rationale for our current efforts to target the soluble epoxide hydrolase enzyme, which degrades bioactive eicosanoids into inactive compounds. A series of potent and selective soluble epoxide hydrolase inhibitors have been characterized in recent years, providing the necessary tools to test this therapeutic strategy in vivo with models of acute and chronic kidney injury. The identification of new treatment approaches for acute and chronic renal injury would benefit the 26 million American adults with chronic kidney disease and millions of others at increased risk of developing this condition.
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 the Department of Cellular and Molecular Pharmacology have expertise in drug and endobiotic metabolism, which provides a rich intellectual environment for these studies. Our studies are also complementary to ongoing efforts in the Roy Lab to develop a biomimetic kidney for testing for renal toxicity. In addition, collaborations with colleagues at the University of California, Davis have been critical for studying novel soluble epoxide hydrolase inhibitors.
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 is deputy editor of Clinical and Translational Science.
Members of the Kroetz Lab have broad expertise in human genetics, molecular and clinical pharmacology, and small-animal models of disease. 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.