Dissecting the Regulation of Zinc-Homeostasis

剖析锌稳态的调节

• 批准号: 7546113
• 负责人: Davin Malasarn
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7546113
• 关键词: Algae; Alzheimer' s Disease; Animals; Bacteria; Biological Models; Biology; Blast Cell; Cardiac; Cells; Chlamydomonas; Chlamydomonas reinhardtii; Computer Simulation; Condition; Consensus Sequence; Copper; Elements; Ensure; Enzymes; Functional disorder; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; Growth; Homeostasis; Homologous Gene; Human; Iron; Libraries; Life; Low Birth Weight Infant; Manganese; Messenger RNA; Metabolism; Metal Binding Site; Metalloproteins; Metals; Micronutrients; Modeling; Neurons; Nucleic Acid Binding; Nutrient; Nutritional; Operative Surgical Procedures; Organism; Pathway interactions; Pattern; Phenotype; Photosynthesis; Plants; Polymerase Chain Reaction; Process; Proteins; Public Health; Range; Reaction; Reactive Oxygen Species; Regulation; Regulon; Reporter; Respiration; Role; Signal Transduction; Staging; Tail; Testing; Time; Toxic effect; Transition Elements; Water; Work; Zinc; Zinc deficiency; base; chelation; cofactor; genetic analysis; immune function; insight; mutant; nutrition; response; transcription factor

DESCRIPTION (provided by applicant): Zinc is an essential nutrient required in over 300 known enzymes by organisms from all domains of life. Zinc deficiency in humans can result in low birth weight, impaired immune function, cardiac dysfunction and acrodermatitus enteropathica. Excess zinc can interrupt other non-zinc metalloproteins and can induce oxidative damage in cells such as neurons, which potentially leads to Alzheimer's Disease. Thus, cells must precisely regulate zinc homeostasis to ensure that they have enough zinc to allow proteins to function while minimizing the amount of excess zinc that can cause damage. The eukaryotic alga Chlamydomonas reinhardtii provides a perfect model system to study the regulation of zinc homeostasis because it can survive under a wide range of zinc-concentrations and contains putative zinc-responsive genes that are conserved in both animals and plants. To understand how Chlamydomonas senses and responds to zinc deficiency or toxicity, I propose the following specific aims: 1) To identify genes that are responsive to distinct stages of zinc nutrition and distinguish the operation of transcriptional vs. post-transcriptional mechanisms, 2) to identify zinc-responsive elements (ZREs) associated with one or more key zinc-responsive targets and assess the role of Crr1, a transcription factor known to regulate both zinc- and copper-responsive genes, in zinc homeostasis and 3) to use a classical genetic approach to identify components of nutritional zinc signal transduction, potentially including regulators and target genes. Studies of Chlamydomonas have already provided valuable insight into the mechanisms of iron and copper homeostasis, and details of zinc-homeostasis regulation will contribute to our broader understanding of how, cells evolved to take advantage of metal cofactors to perform the vital functions of life. Public Health Relevance: Zinc is an essential nutrient required in abundance by organisms ranging from bacteria to humans. Zinc is required by over 300 known enzymes, including those involved in respiration, transcription and photosynthesis. In this work, mechanisms of zinc-sensing and adaptive response will be unraveled to understand how cells recognize and adjust to zinc deficiency and toxicity.

描述（由申请人提供）：锌是来自生命所有领域的生物体中300多种已知酶所需的必需营养。人类的锌缺乏会导致低出生体重，免疫功能受损，心脏功能障碍和肠道肌张力障碍。多余的锌会中断其他非锌金属蛋白，并可以在神经元等细胞中诱导氧化损伤，这可能导致阿尔茨海默氏病。因此，细胞必须精确调节锌稳态，以确保它们具有足够的锌以允许蛋白质起作用，同时最大程度地减少可能造成损害的多余锌的量。真核生物藻类衣原体Reinhardtii提供了一个完美的模型系统来研究锌稳态的调节，因为它可以在广泛的锌浓度下生存，并包含在动物和植物中保守的推测锌响应基因。 To understand how Chlamydomonas senses and responds to zinc deficiency or toxicity, I propose the following specific aims: 1) To identify genes that are responsive to distinct stages of zinc nutrition and distinguish the operation of transcriptional vs. post-transcriptional mechanisms, 2) to identify zinc-responsive elements (ZREs) associated with one or more key zinc-responsive targets and assess the role of Crr1, a transcription已知可以调节锌和铜响应基因的因素，在锌稳态中，3）使用经典的遗传方法来鉴定营养锌信号转导的成分，可能包括调节剂和靶基因。关于衣原体的研究已经为铁和铜稳态的机制提供了宝贵的见解，锌蜂窝状调节的细节将有助于我们对细胞如何利用金属辅助因子来执行生命的重要功能的更广泛理解。公共卫生相关性：锌是从细菌到人类的生物不等的重要营养物质。锌是300多种已知酶所需的，包括参与呼吸，转录和光合作用的酶。在这项工作中，将阐明锌感应和自适应反应的机制，以了解细胞如何识别和适应锌缺乏和毒性。