KATHLEEN M. GIACOMINI, Ph.D., Professor of Biopharmaceutical Sciences and Pharmaceutical Chemistry

Targeting of a molecule such as a drug to a biological receptor necessitates a knowledge of the cellular and molecular events involved in the transport of the molecule across the epithelia involved in its absorption, distribution and elimination. Research in Dr. Giacomini’s laboratory focuses on understanding the molecular events involved in the transport of drug molecules across epithelial barriers. Particular emphasis is placed on understanding the mechanisms involved in the transport of organic cations and nucleosides. Studies ascertaining the biological relevance of these transport processes to drug disposition are carried out.

Highlight of Recent Research Accomplishments:

1. Cloning and characterization of the first human organic cation transporter, hOCT1. The studies provided the first information on the molecular structure and functional properties of a human polyspecific (broad substrate selectivity) organic cation transporter. Currently, we have transfected the transporter into mammalian cells and are studying the mechanisms involved in transport of various drugs via the transporter. In addition, we have cloned the first organic cation transporter from rabbit, the species in which most of the physiologic studies of organic cation transport have been performed. The availability of this clone will allow us to identify physiologically relevant mechanisms of organic cation transport.
2. Cloning and characterization of a novel isoform rOCT1A of the rat organic cation transporter, rOCT1. Genomic sequencing revealed that this isoform is a splice variant and has set the stage for understanding the mechanisms that are responsible for the diversity in organic cation transport between tissues and within a given tissue. Current studies are underway with truncated mutants of organic cation transporters to understand the functional role of the splice variant.
3. Cloning and functional characterization of the first human nucleoside transporter, hSPNT1. The transporter is a Na⁺-dependent purine selective transporter. Ongoing studies in transfected cells have allowed us to characterize the function of the transporter in detail. Northern analysis indicates that the transporter is distributed widely in human tissues and may play a role in nucleoside salvage, transepithelial flux of nucleosides and in the termination of purinergic effect.
4. Molecular identification of the nucleoside binding site. Through a series of chimera constructs, we have identified a region, i.e., transmembrane 8 and 9 of the nucleoside transporters which confer purine or pyrimidine substrate selectivity. These studies greatly advance the understanding of the molecular events involved in the transport of nucleosides.

SELECTED PUBLICATIONS:

1. Urban TJ, Giacomini KM, Risch N. Haplotype structure and ethnic-specific allele frequencies at the OCTN locus: implications for the genetics of Crohn's disease. Inflamm Bowel Dis, 11(1):78-79, 2005.
2. Ferrin TE, Huang CC, Greenblatt DM, Stryke D, Giacomini KM, Morris JH. Enhancing data sharing in collaborative research projects with DASH. Pac Symp Biocomput, 260-271, 2005.
3. Badagnani I, Chan W, Castro RA, Brett CM, Huang CC, Stryke D, Kawamoto M, Johns SJ, Ferrin TE, Carlson EJ, Burchard EG, Giacomini KM. Functional analysis of genetic variants in the human concentrative nucleoside transporter 3 (CNT3; SLC28A3). Pharmacogenomics J, 2005.