In response to RFA:ES-01-002, this is an application to become a member of the NIEHS-sponsored Toxicogenomics Research Consortium. The have proposed a highly integrated plan to explore the transcriptional responses of a variety of organisms, including humans, to a broad range of toxic agents found in the environment. Transcriptional profiling is expected to reveal a truly global view of how cells, tissues and animals attempt to recover, not always successfully from environmental insults. The investigators hope to learn what features of environmentally induced transcriptional responses are predictive of success or failure, and in addition to learn what features correlate with specific outcomes of toxic exposures, for instance, cell death, apoptosis, mutagenesis and carcinogenesis. The model environmental agents to be studied are Aflatoxin B1 and its metabolites, plus a range of SNI and SN2 alkylating agents. Together these agents are representative of toxic agents found in the external environment, food supply, the endogenous cellular environment, and the cancer chemotherapy clinic. The model organisms and cell systems whose transcriptional responsiveness will be scrutinized include E. coli, S. cerevisiae, cultured rodent and human cell lines, engineered rat and mouse liver tissues, rats and mice. The investigators have integrated an in vitro tissue engineering Project into this application with the goal of developing an alternative to using animals to test for toxicity and carcinogenicity. It seems to the investigators that appropriate transcriptional responsiveness in this system represents a rigorous test of its similarity to in vivo tissues. Two platforms for mRNA profiling will be employed, namely, Affymetrix GeneChip DNA oligonucleotide microarrays, and cDNA arrays fabricated in the MIT BioMicro Center. The Microarraying and Bioinformatics Core will have its center of gravity in the MIT BioMicro Center, and this Core will serve as the focal point for three Research Projects and the Toxicology Research Core Project (TRCP). The TRCP activities will be closely aligned with the activities of the other 4 or 5 members of the Toxicogenomics Research Consortium. Together the overarching goals will be to establishing good working practices in transcriptional profiling as it relates to the area of toxicogenomics, and to contribute to the development of an extensive relational database as a repository for high quality data emerging from the field of toxicogenomics. The investigators anticipate that this research will uncover a myriad of hitherto unknown ways in which cells respond to environmental agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19ES011399-04
Application #
6786790
Study Section
Special Emphasis Panel (ZES1-LKB-E (RT))
Program Officer
Suk, William
Project Start
2001-09-30
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
4
Fiscal Year
2004
Total Cost
$1,560,607
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Type
Organized Research Units
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
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