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

金属调节因子 1 (MTF-1) 在发育和应激反应中的作用

• 批准号: 7571754
• 负责人: Matthew J. Jenny
• 金额: $ 7.94万
• 依托单位: WOODS HOLE OCEANOGRAPHIC INSTITUTION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-29 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571754
• 关键词: 2-tert-butylhydroquinone; Animal Model; Award; Binding; Binding Proteins; Bioinformatics; Cadmium; Cell Differentiation process; Cellular Stress; Chromatin; Computer Analysis; Consultations; Development; Dominant-Negative Mutation; Dose; Drug Metabolic Detoxication; Embryo; Embryonic Development; Erythroid; Future; Gene Activation; Gene Combinations; Gene Expression; Gene Expression Profiling; Gene Targeting; Genes; Genomics; Goals; Heat-Shock Proteins 70; Homeostasis; Hypoxia; Institution; Investigation; Ischemia; Knock-out; Laboratory Research; Larva; Learning; Liver; Measurement; Mentors; Metal exposure; Metals; Microarray Analysis; Microinjections; Modeling; Molecular; Molecular Profiling; Molecular Toxicology; Mus; Mutation; Neurodegenerative Disorders; Neurons; Nuclear; Oligonucleotide Microarrays; Oligonucleotides; Oxidative Stress; Phase; Phenotype; Play; Principal Investigator; Promoter Regions; Property; Proteins; RNA; Regulation; Regulator Genes; Repression; Research; Research Personnel; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Staging; Stress; Techniques; Testing; Time; Tissue Differentiation; Tissues; Toxicogenomics; Toxicology; Training; Transactivation; Transcriptional Activation; Transcriptional Regulation; Transgenic Organisms; Universities; Wood material; Zebrafish; Zinc; Zinc Fingers; biological adaptation to stress; enhanced green fluorescent protein; experience; functional genomics; in vivo; insight; knock-down; novel; novel strategies; prevent; promoter; relating to nervous system; research study; response; stressor; transcription factor; tumor progression

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.

描述（由申请人提供） 金属反应元件结合转录因子-1（MTF-1）是一种广泛表达的转录因子，其在涉及金属稳态、胚胎发育、肿瘤进展和氧化应激或缺氧信号传导的多种基因的调节中起主要作用。本研究的总体目标是表征MTF-1与核红细胞2 p45相关因子2（NRF 2）的重叠作用，NRF 2是调节氧化应激反应的主要转录因子，在应激反应基因的发育和转录共调节中。该奖项的研究者的目标是获得先进的培训，在分子和转基因技术利用斑马鱼作为模式生物的发育毒理学。这些技术将包括吗啉敲低基因表达，转基因斑马鱼系的发展，基因表达谱与寡核苷酸微阵列，和先进的生物信息学技术的微阵列分析和计算启动子分析。研究者将通过将这些技术应用于在细胞对金属或氧化应激的反应中发挥基本作用的转录因子的研究来扩展环境/生态毒理基因组学的背景。这方面的经验将有助于研究者在未来的目标，建立一个独立的研究实验室，分子和基因组技术将被用来继续研究发育和分子毒理学和基因调控网络。该奖项导师阶段的培训将由Mark Hahn博士（伍兹霍尔海洋研究所，WHOI）指导，他是一位国际公认的分子毒理学家，在各种模式生物的转录因子表征方面拥有20年的研究经验。WHOI是世界著名的科学研究中心。在Hahn博士的指导下，并与埃尔伍德林尼博士（杜克大学）协商，研究者将充分表征MTF-1的反式激活结构域，并产生一个生殖系转基因斑马鱼，通过显性阴性构建体的表达抑制内源性MTF-1信号传导。除了学习先进的斑马鱼技术外，辅导阶段的时间还将包括通过正式课程和研讨会进行的额外培训，以及将帮助研究人员过渡到独立研究人员的进一步指导。

项目成果

Inhibition of endogenous MTF-1 signaling in zebrafish embryos identifies novel roles for MTF-1 in development.

斑马鱼胚胎中内源性 MTF-1 信号传导的抑制确定了 MTF-1 在发育中的新作用。

• DOI: 10.1016/j.bbamcr.2014.04.015
• 发表时间: 2014
• 期刊: Biochimica et biophysica acta
• 作者: O'Shields,Britton;McArthur,AndrewG;Holowiecki,Andrew;Kamper,Martin;Tapley,Jeffrey;Jenny,MatthewJ
• 通讯作者: Jenny,MatthewJ