Our lab focuses on membrane transporters, particularly in understanding their endogenous roles and their mechanisms on drug actions.
In the UC San Francisco lab of Kathy Giacomini, PhD, research projects focus on the following studies related to membrane transporters:
Membrane transporters are a collection of mechanisms that determine how small molecules pass through biological membranes. They can help us understand and better predict how drugs behave in terms of:
- Absorption—how quickly the body ingests and processes it.
- Distribution—how widely throughout the body it spreads.
- Elimination—how quickly the body removes it.
- Response—did the drug have the intended effect?
- Toxicity—when is too much of a drug harmful?
This knowledge has a wide-reaching effect on global health in that pharmacists, nurses, dentists, and doctors worldwide are better able to predict how their patients will respond to medications by more safely and more precisely applying them.
Genetic differences in membrane transporters are increasingly recognized as key determinants of therapeutic drug response or toxicity. Identifying these variants and understanding how they affect drug response in humans is challenging. Our lab is addressing this by studying:
- Genomewide association
- Candidate transporter genes
- Cells and knockout mice
Since 2007, genomewide association studies (GWAS) have resulted in the discoveries of many genetic factors which determine risk for human disease and variation in human traits. Genotyping and DNA-sequencing technologies have significantly advanced the field of human genetics. Genome-wide genotyping arrays (targeted, exome-, or whole-genome sequencing) coupled with imputation that uses public information from ethnically diverse populations enables us to get a comprehensive picture of genetic variation in an individual. Multiple large clinical cohorts ranging from clinical trials to electronic medical records have advanced the field of discoveries for human disease as well as drug response traits. Our lab is working to:
- Discover genetic variation in patients with gout or type 2 diabetes that leads to changes to measurable phenotypes (traits) relevant to allopurinol and metformin, respectively.
- Understand the mechanisms between variations in the membrane transporter locus discovered in GWAS or candidate gene studies and drug response.
The UCSF School of Pharmacy is an ideal place for pharmacogenomics research. The Giacomini Lab is part of the Department of Bioengineering and Therapeutic Sciences, which has been the home of the Pharmacogenomics of Membrane Transporters (PMT) project in the National Institutes of Health (NIH) Pharmacogenomics Research Network (PGRN) from 2000 to 2015. The Giacomini Lab continues to be part of the NIH PGRN, and also leads the PGRN-RIKEN collaboration, a global pharmacogenomics consortium. Collaborations among members of the UCSF Institute for Human Genetics and the Kaiser Permanente Division of Research in nearby Oakland, California, provide a rich environment for these pharmacogenomics 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.
SoLute Carrier Superfamily (SLC) consists of 52 families and about 380 transporters that primarily function as facilitated influx pumps. This superfamily transports a wide array of substrates across biological membranes to exhibit critical roles in physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics. More interestingly, there are several prescription drugs which inhibit SLC transporters to treat human diseases. For example, inhibition of sodium-glucose transporters (SGLTs) lowers blood glucose, hence it is used to treat Type 2 diabetes.
Because of many known mutation or genetic polymorphisms in these SLC transporters, which cause various rare and common diseases, this exciting field has led our group to focus our research on:
- Endogenous roles of organic cation transporters
- Discoveries of novel targets and substrates/inhibitors of pharmacologically important SLC transporters
The UCSF School of Pharmacy and School of Medicine are ideal places for pharmacology and translational research.
- Giacomini is a co-founder of the International Transporter Consortium (ITC), along with her collaborators in industry and regulatory bodies. The ITC has contributed a large body of scientific knowledge to the communities about membrane transporters and their relevance to clinical pharmacology and research by regulatory and basic research scientists.
- UCSF is strongly affiliated with Gladstone Institutes, and one of Gladstone’s core facilities is the Transgenic Gene Targeting Core, which has contributed valuable resources to support the studies needed for the creation of a mouse model to study endogenous roles of organic cation transporters.
- The UCSF Small Molecule Discovery Center (SMDC) has provided valuable resources, expertise, and technologies to allow discoveries of small molecules as inhibitors or substrates of SLC transporters.
Kathy Giacomini, PhD, is a world-renowned clinical pharmacologist and transporter biologist. She is an expert in pharmacokinetics and drug transport and is a world leader in pharmacogenomics research, understanding the mechanisms for interindividual variation in drug response and toxicity. Giacomini has contributed enormously to the education and training of her dedicated students, postdocs, senior researchers and visiting scientists, which has led her to be a recipient of numerous distinguished awards, including the postdoctoral mentor award.
Members of the Giacomini Lab have broad expertise in pharmacogenomics, transporter biology, molecular modeling and clinical pharmacology. The lab environment along with Giacomini’s mentorship provides a rich training ground for students and postdoctoral scholars, along with opportunities for collaborations with UCSF faculty members and national and international collaborators.