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Mechanism of the Transcriptional Response to Transition Metals

过渡金属的转录反应机制

基本信息

批准号：
8068881
负责人：
MICHAEL Thomas MARR
金额：
$ 30.22万
依托单位：
BRANDEIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8068881
关键词：
Address Affect Binding Binding Proteins Binding Sites Biological Biological Models Cadmium Cd thionein Cell physiology Cells Complex Connective Tissue Copper Discrimination Disease Dose Drosophila genome Drosophila genus Elongation Factor Equilibrium Free Radicals Gene Expression Profile Gene Expression Regulation Gene Targeting Generations Genes Genetic Transcription Genomics Goals Growth Health Hepatolenticular Degeneration Homeostasis Human Immunoprecipitation Individual Iron Kidney Knowledge Lead Left Libraries Liver Mammalian Cell Mediator of activation protein Menkes Kinky Hair Syndrome Mercury Metabolic Metallothionein Metals Microarray Analysis Modeling Nature Nervous system structure Normal Cell Nutrient Nutritional Requirements Organism Pathology Physiological Play Positioning Attribute Proteins RNA Interference Regulation Regulon Response Elements Role Sequence-Specific DNA Binding Protein Signal Transduction Staging Stimulus Stress System Toxic effect Transcript Transcription Elongation Transcription Initiation Transcriptional Activation Transcriptional Regulation Transition Elements Work Zinc base brain tissue cohort in vitro Assay interest prevent programs promoter response sensor toxic metal transcription factor transcription factor MTF-1

项目摘要

DESCRIPTION (provided by applicant): Essential divalent transition metals such as zinc, copper, and iron play important structural and catalytic roles in over 300 proteins. However, these and other transition metals also pose a potential threat to an organism. Left unchecked these metals can catalyze the generation of free radicals that damage all types of biological molecules. Transition metals must be kept in a physiological window. Diseases like Wilson's disease and Menke's disease demonstrate that either too much or too little metal can lead to pathologies of the liver, kidney, nervous system and connective tissues. Clearly metal homeostasis is an important aspect of cellular function. A major part of this control occurs at the level of transcription. One of the central players in this regulation is the metal response element binding protein (MTF-1). MTF-1 is a sequence specific DNA binding protein that perceives the metal status of a cell and activates genes accordingly. A good deal is known about MTF-1 itself, but very little is known about the protein co-factors that help MTF-1 efficiently activate transcription. We will use an RNAi based screen, in the Drosophila model system, to determine what protein co-factors are required for metal stimulated transcription. In addition we will characterize the physical and functional interactions between MTF-1 and these protein co-factors using a combination of cell based and in vitro assays. Finally we will identify the MTF-1 binding sites across the Drosophila genome to define the MTF-1 regulon that responds to metal stimuli. The long-term objective of our studies is to understand how a cell, in response to a diverse set of metals, differentially regulates the appropriate metal responsive genes to control metal homeostasis. PUBLIC HEALTH RELEVANCE: Humans have a nutritional requirement for essential metals for normal growth and health. But in high doses many of these metals become toxic. Understandably, there is also a need to keep these metals in balance. We are studying the genes that help maintain this equilibrium. The long term goal is to understand how deregulation of these same genes contributes to metal induced disease.

描述（由申请人提供）：锌、铜和铁等必需的二价过渡金属在 300 多种蛋白质中发挥着重要的结构和催化作用。然而，这些和其他过渡金属也对生物体构成潜在威胁。如果不加以控制，这些金属会催化自由基的产生，从而损害所有类型的生物分子。过渡金属必须保存在生理窗口内。威尔逊氏病和门克氏病等疾病表明，金属过多或过少都会导致肝脏、肾脏、神经系统和结缔组织病变。显然，金属稳态是细胞功能的一个重要方面。这种控制的主要部分发生在转录水平。该调节的核心参与者之一是金属反应元件结合蛋白（MTF-1）。 MTF-1 是一种序列特异性 DNA 结合蛋白，可感知细胞的金属状态并相应地激活基因。人们对 MTF-1 本身了解甚多，但对帮助 MTF-1 有效激活转录的蛋白质辅助因子知之甚少。我们将在果蝇模型系统中使用基于 RNAi 的筛选，以确定金属刺激转录所需的蛋白质辅助因子。此外，我们将结合细胞和体外测定来表征 MTF-1 和这些蛋白质辅助因子之间的物理和功能相互作用。最后，我们将确定果蝇基因组中的 MTF-1 结合位点，以定义对金属刺激做出反应的 MTF-1 调节子。我们研究的长期目标是了解细胞如何响应多种金属，差异性地调节适当的金属响应基因以控制金属稳态。公共健康相关性：人类对正常生长和健康所必需的金属有营养需求。但在高剂量下，许多这些金属会变得有毒。可以理解的是，还需要保持这些金属的平衡。我们正在研究有助于维持这种平衡的基因。长期目标是了解这些相同基因的失调如何导致金属诱发的疾病。