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）：锌是所有生命领域的生物体在300多种已知酶中所需的必需营养素。人类锌缺乏可导致低出生体重、免疫功能受损、心脏功能障碍和肠病性肢端皮炎。过量的锌可以中断其他非锌金属蛋白，并可以诱导细胞如神经元的氧化损伤，这可能导致阿尔茨海默病。因此，细胞必须精确地调节锌的体内平衡，以确保它们有足够的锌来允许蛋白质发挥作用，同时最大限度地减少可能导致损伤的过量锌。真核生物莱茵衣藻（Chlamyeliumreinhardtii）是研究锌稳态调节的理想模型，它能在较宽的锌浓度范围内存活，并含有动物和植物中保守的锌应答基因。为了了解衣原体如何感知和应对锌缺乏或毒性，我提出了以下具体目标：1）鉴定对锌营养的不同阶段有响应的基因，并区分转录机制与转录后机制的操作，2）鉴定与一个或多个关键锌响应靶标相关的锌响应元件（ZRE），并评估Crr 1的作用，已知在锌稳态中调节锌和铜响应基因的转录因子，和3）使用经典遗传方法来鉴定营养锌信号转导的组分，可能包括调节剂和靶基因。对衣原体的研究已经为铁和铜稳态的机制提供了有价值的见解，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因子来执行生命的重要功能。公共卫生相关性：锌是从细菌到人类的生物体大量需要的必需营养素。超过300种已知的酶需要锌，包括那些参与呼吸，转录和光合作用的酶。在这项工作中，锌敏感和适应性反应的机制将被解开，以了解细胞如何识别和调整锌缺乏和毒性。