CARCINOGENESIS AND TOXICOGENOMICS RESEARCH CORE

Research Focus of the Core

The Carcinogenesis and Toxicogenomics Research Core is based in part around the historical research interests of several established investigators (Bailey, Bayne, Buhler, Thorgaard, Williams), with collective expertise in biochemistry, molecular biology, genetics, pathology and carcinogenesis. The focus of this group has been in the development and application of rainbow trout and zebrafish as aquatic models for the study of carcinogenesis and its modulation by dietary and environmental factors. The development of clonal trout lines and triploid individuals has lent new approaches to the study of cancer genetics in the trout model. The complexity of the cancer process has lent itself well to progress through synergistic interactions, where this group of scientists has combined their individual areas of expertise to the greater advancement in cancer research with aquatic, rodent, and human subjects. The primary mechanism through which synergism has been met, and will continue to occur, is through the design and submission of cancer-based research applications involving two or more investigators within the Center, and the co-authorship of research publications resulting from those grants. This year we have added a new investigator (Bayne) with interests in aquatic immune systems, and their involvement in a variety of chemical and physiological stress responses. This will offer a new opportunity, heretofore unavailable to us, to expand carcinogenesis and ecotoxicologic research in aquatic models to consider the role of the immune system.

A newly emerging research interest within the Center lies in the use of toxicogenomics approaches in the study of environmental disease with aquatic organisms. While aquatic vertebrates such as rainbow trout provide many unique advantages in the study of environmental disease, we have recognized that absence of a good genetic map, a genome sequence, and scarcity of the protein and nucleotide reagents commonly available for mammalian species pose significant impediments to the continued understanding of comparative mechanisms and their extrapolation to the human condition. Progress elsewhere in zebrafish genome sequencing will soon resolve many of these issues for this species. For the trout, although genome sequencing is not in the immediate offing, researchers within the core are making significant progress in providing a genetic map including enumeration and placement of protooncogenes and tumor suppressor genes in this species. Additionally, collaborative efforts within the core and with investigators elsewhere are expected soon to provide the first generation of gene chips for microarray analyses with the rainbow trout. The development of trout microarray tools is being led by Dr. Bayne, with initial center efforts funded through a joint pilot project with Dr. Bailey and a joint NIEHS programmatic development grant to the four NIEHS MFBS Centers. Although this newly emerging interest is nominally focused within the Carcinogenesis and Toxicogenomics Core, the approaches and tools derived will certainly serve to strengthen research interactions between the two Research Cores within this Center.>

Areas of Interaction

A principal source of scientific interaction within this core for the next 5-year period derives from Program Project CA90890-01A2, “Comparative Mechanisms of Cancer Chemoprevention”. This P01 involves three members of the Core (G. Bailey, P01 PI and Director subproject 1; D. Williams, Director of subproject 2, J. Hendricks, Co-I of subproject 1), as well as Dr. Pereira (Co-I of subprojects 1 and 2) from the Environmental Health Sciences Center. The P01 ties together interests and expertise from the OSU MFBS Center, the EHS Center (Pereira, Statistics Core; Hedstrom, Pathology Core), and the Linus Pauling Institute (R. Dashwood, Director of subproject 3). It also involves collaboration between the NIEHS Centers at OSU and the NIEHS Center at Johns Hopkins University (T. Kensler, collaborator and External Advisor; J. Groopman, collaborator). Subproject 2 brings in a young faculty member, Dr. Rosita Rodriguez, as Co-I and a potential new Investigator for the Center. Many additional interactions are slated to occur, including interactions with the Neuro- and Developmental Toxicology Research Core on the toxicity and metabolism of methyl dithiocarbamate (metam sodium) in zebrafish (Tanguay, Bailey, Buhler), use of NMR methods in analysis of carcinogen-chlorophyll complexes (Gerwick, Bailey, Williams), structural analysis of indoles (Williams, Gerwick) to mention a few. Future research applications now in the planning stage include an application to extend the 42,000 trout cancer dose-response studies, that will require collaborations between Dr. Williams (metabolism), Pereira (statistics), Hendricks (fish pathology), and Bailey (carcinogenesis, biomarkers). A possible NCI RFA application using clonal trout lines to investigate diet/methylation interactions in carcinogenesis is also under discussion (Thorgaard, Williams).