Giacomini Lab
The Giacomini research group focuses on expanding our understanding of the biological and pharmacological roles of membrane transporters in the Solute Carrier (SLC) Superfamily. Membrane transporters are of great importance, as they play a major role in disposition and distribution of solutes including drugs, environmental toxins and other xenobiotics. Major questions addressed in the laboratory include: What is the in vivo role of membrane transporters in drug disposition and response? How does genetic variation in membrane transporters affect clinical drug response and human disease? What is the endogenous role of membrane transporters? Currently, the Giacomini group is leading an effort to deorphanize transporters in the SLC22 family, a major family within the SLC superfamily responsible for the absorption, distribution, and elimination of xenobiotics. Further, we are assessing the function of genetic variants in membrane transporters in the SLC21 and SLC22 families and their implications to human disease and drug response. Research ventures, ranging from basic discovery to clinical studies, have demonstrated that rare and common genetic variants of membrane transporters contribute to differences in drug response and human disease in ethnically diverse populations.
The Critical Path Initiative Research represents a part of FDA's strategy for transforming the way FDA-regulated medical products are developed and evaluated. As transporters play a major role in drug absorption, disposition and response and are important targets of drug-drug interactions, the FDA funded efforts in the Giacomini laboratory to create the original TransPortal, which housed information exclusively on drug interactions with human transporters. This database has been greatly expanded in this version to include updated information on rodent and monkey drug transporter interactions as well as new information on the interaction of other ligands with membrane transporters.
Hamdoun Lab
Regulated movement of small molecules across cellular membranes is a defining feature of life. Understanding the biological mechanisms that govern these regulated movements informs a diverse array of questions from defining the sources and sinks of molecular signals in development, to predicting the uptake and elimination of pharmaceuticals and environmental toxicants. The overarching theme of research in the Hamdoun lab is on the small molecule transporters (ABCs and SLCs) present in all organisms from bacteria to man. In pursuit of this problem, they have leveraged a diverse array of approaches ranging in scale from biochemical, e.g., x-ray co-crystallography, to organismal, e.g., the generation of novel drug transporter mutant model organisms. Among these model organisms, the lab is best known for its work with the sea urchin embryo.
This project has been supported by the Hamdoun lab’s works in the NIEHS program on Oceans and Human Health. This work has revealed that environmental chemicals, to which humans are routinely exposed, can interfere with xenobiotic transporters - termed Transporter Interfering Chemicals (TICs). This group reported the first structure of P-gp (ABCB1) in complex with an environmental pollutant, in this case a polybrominated diphenyl ether (flame retardant). The significance of the structure was to reveal evolutionarily conserved residues that may mediate TIC interaction in other species, potentially providing a conceptual framework for understanding the impact on bioaccumulation. TICs are a new class of environmental contaminant – similar to endocrine disrupting compounds – that act indirectly at low doses to influence drug sensitivity. TICs could act to modify uptake and/or elimination of relevant XT substrates - including prescription drugs, endogenous metabolites, and environmental chemicals handled by XTs in humans and wildlife.
Nicklisch Lab
Biochemical and molecular adaptations of cell metabolism are an important organismal response to environmental stressors, including biological and chemical stressors. In an everchanging environment, organismal stress response must be versatile and evolve to secure cellular integrity and homeostasis. The Nicklisch lab seeks to understand the molecular mechanisms underlying short-term adaptations and long-term evolution of cellular stress response proteins, including metabolic enzymes and xenobiotic transporters. A special interest is in the identification of biochemical mechanisms governing functional and structural conservation of these first-line defense proteins when challenged with multiple stressors, such as xenobiotics, oxidative and thermal stress.
Using high-throughput in silico and standardized in vitro enzyme and transporter/xenobiotic interaction assays as proxies, the lab seeks to identify and predict the molecular mechanisms of xenobiotic bioaccumulation and toxicity in humans and other organisms. The lab further applies ligand- and structure-based approaches to characterize and predict the role of metabolic enzymes and xenobiotic transporters in environmental chemical interactions with drugs and physiological substrates.
Currently, the group is investigating how chemical pesticides interact with ABC drug transporters in beneficial insect pollinators versus human disease vectors to advance precision pest control and improve pollinator protection. Another key project in the lab focuses on the identification of novel structural motifs in physiological and xenobiotic ligands that determine recognition or non-recognition by metabolic enzymes and transporters. Understanding how pharmaceuticals, natural products, herbs, environmental chemicals, and mixtures thereof interact with evolutionarily conserved cellular defense and stress response systems can inform the rational design and development of more bioavailable therapeutics while reducing toxicity of these and other environmental chemicals to non-target organisms.
Citing information:
If you use any information from this website, please cite the following publication:
Morrissey KM, Wen CC, Johns SJ, Zhang L, Huang SM, Giacomini KM, "The UCSF-FDA TransPortal: A Public Drug Transporter Database", Clinical Pharmacology and Therapeutics (2012) 92(5):545-6.
