Metal-Regulatory Factor 1 (MTF-1) Role in Development and Stress Response

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DESCRIPTION (provided by applicant) The metal response element-binding transcription factor-1 (MTF-1) is a ubiquitously expressed transcription factor that plays a primary role in the regulation of a variety of genes involved in metal homeostasis, embryonic development, tumor progression, and oxidative stress or hypoxia signaling. The overall objective of this research is to characterize the overlapping role of MTF-1 with Nuclear erythroid 2 p45-related factor 2 (NRF2), the primary transcription factor for regulating the oxidative stress response, in development and transcriptional co-regulation of stress responsive genes. The investigator's goal for this award is to obtain advanced training in molecular and transgenic techniques utilizing the zebrafish as a model organism for developmental toxicology. These techniques will include morpholino knockdown of gene expression, development of transgenic zebrafish lines, gene expression profiling with oligonucleotide microarrays, and advanced bioinformatic techniques for microarray analysis and computational promoter analysis. The investigator will expand background in environmental/ecological toxicogenomics by applying these techniques to the study of transcription factors that play fundamental roles in the cellular response to metal or oxidative stress. This experience will assist the investigator in the future goal of establishing an independent research laboratory, where molecular and genomic techniques will be utilized to continue research in developmental and molecular toxicology and gene regulatory networks. Training during the mentor phase of this award will be directed by Dr. Mark Hahn (Woods Hole Oceanographic Institution, WHOI), an internationally recognized molecular toxicologist with two decades of research experience in the characterization of transcriptipon factors in a variety of model organisms. WHOI is a world-renowned center of scientific research. Under the guidance of Dr. Hahn, and with consultation from Dr. Elwood Linney (Duke University), the investigator will fully characterize the transactivation domain of MTF-1 and generate a germline transgenic zebrafish that inhibits endogenous MTF-1 signaling through the expression of a dominant-negative construct. In addition to learning advanced zebrafish techniques, time in the mentored phase will involve additional training through formal coursework and seminars, as well as further guidance in grantsmanship that will assist the investigator in transition to an independent researcher.