Dissecting the Regulation of Zinc-Homeostasis

剖析锌稳态的调节

• 批准号: 7799763
• 负责人: Davin Malasarn
• 金额: $ 5.05万
• 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/7799763
• 关键词: Algae; Alzheimer' s Disease; Animals; Bacteria; Biological Models; Biology; Blast Cell; Cardiac; Cells; Chlamydomonas; Chlamydomonas reinhardtii; Computer Simulation; 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; Organism; Pathway interactions; Pattern; Phenotype; Photosynthesis; Plants; Process; Proteins; 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; operation; oxidative damage; public health relevance; 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）：锌是生命各领域生物体 300 多种已知酶所需的必需营养素。人类缺锌会导致低出生体重、免疫功能受损、心脏功能障碍和肠病性肢皮炎。过量的锌会干扰其他非锌金属蛋白，并可能引起神经元等细胞的氧化损伤，这可能导致阿尔茨海默病。因此，细胞必须精确调节锌稳态，以确保它们有足够的锌来使蛋白质发挥作用，同时最大限度地减少可能造成损害的过量锌的量。真核藻类莱茵衣藻为研究锌稳态调节提供了一个完美的模型系统，因为它可以在各种锌浓度下生存，并且含有在动物和植物中保守的推定锌响应基因。为了了解衣藻如何感知和响应锌缺乏或毒性，我提出以下具体目标：1）识别对锌营养不同阶段有反应的基因，并区分转录与转录后机制的运作，2）识别与一个或多个关键锌反应靶标相关的锌反应元件 (ZRE)，并评估 Crr1（一种已知可调节锌和铜反应基因的转录因子）在锌中的作用稳态；3) 使用经典的遗传方法来识别营养锌信号转导的成分，可能包括调节因子和靶基因。对衣藻的研究已经为铁和铜稳态机制提供了宝贵的见解，而锌稳态调节的细节将有助于我们更广泛地了解细胞如何进化以利用金属辅助因子来执行生命的重要功能。公共健康相关性：锌是从细菌到人类等生物体大量需要的必需营养素。超过 300 种已知酶需要锌，包括参与呼吸、转录和光合作用的酶。在这项工作中，将揭示锌感应和适应性反应的机制，以了解细胞如何识别和适应锌缺乏和毒性。