Metal Homeostasis in Yeast

描述（由申请人提供）：概述铁（Fe）是作为多种酶和蛋白质的生化辅因子的必需元素，所述酶和蛋白质在氧转运、线粒体氧化磷酸化、DNA复制和修复、中间代谢、脂质代谢、染色质修饰和许多其它关键生理过程中起作用。铁缺乏症是地球上最常见的营养缺乏症，其健康后果包括贫血、生长发育迟缓、运动和认知功能异常、免疫功能下降、体温调节缺陷、疲劳和工作表现下降。虽然铁缺乏导致严重的健康后果，详细的分子机制，允许分级反应的范围内的铁缺乏的严重程度还没有得到很好的理解。该建议描述了研究途径，以了解真核细胞响应和适应铁缺乏的基本机制。第一个具体的目标概述了实验，以破译的机制，酵母Cth 1和Cth 2蛋白质差异靶向mRNA的降解反应铁缺乏，导致细胞代谢适应，使细胞能够科普减少铁的可用性。第二个具体目标描述了实验，以了解如何表达的Cth 1和Cth 2蛋白是精致的微调，在响应铁缺乏，这种调节的生理重要性，相对于铁稳态和其潜在的联系，在细胞周期进程的变化。考虑到铁缺乏症的普遍发生及其对妇女和儿童健康的不成比例的影响，本申请中概述的研究将提供关于细胞稳态响应铁缺乏症的机制的基本重要信息。公共卫生相关性：铁缺乏症是地球上最常见的营养缺乏症，其健康后果包括贫血、生长发育迟缓、运动和认知功能异常、免疫功能下降、体温调节缺陷、疲劳和工作表现下降。鉴于铁缺乏症的普遍发生及其对妇女和儿童健康的不成比例的影响，本申请中概述的研究将提供有关细胞适应铁缺乏症的机制的重要信息。

DESCRIPTION (provided by applicant): Summary Iron (Fe) is an essential element that serves as a biochemical co-factor for a wide variety of enzymes and proteins that function in oxygen transport, mitochondrial oxidative phosphorylation, DNA replication and repair, intermediary metabolism, lipid metabolism, chromatin modification and a host of other critical physiological processes. Fe deficiency is the most common nutritional deficiency on earth, with health consequences that include anemia, delayed growth and development, abnormal motor and cognitive function, decreased immune function, thermoreguatory defects, fatigue and decreased work performance. While Fe deficiency leads to severe health consequences, the detailed molecular mechanisms that allow graded responses to a range of severity of Fe deficiency are not well understood. This proposal describes avenues of investigation to understand fundamental mechanisms whereby eukaryotic cells respond and adapt to Fe deficiency. The first specific aim outlines experiments to decipher the mechanisms by which the yeast Cth1 and Cth2 proteins differentially target mRNAs for degradation in response to Fe deficiency, leading to cellular metabolic adaptation to allow cells to cope with reduced Fe availability. The second specific aim describes experiments to understand how expression of the Cth1 and Cth2 proteins is exquisitely fine-tuned in response to Fe deficiency, the physiological importance of this regulation with respect to Fe homeostasis and its potential link to changes in cell cycle progression. Given the common occurrence of Fe deficiency and its disproportionate affects on the health of women and children, the studies outlined in this application will provide fundamentally important information on the mechanisms by which cells homeostatically respond to Fe deficiency. PUBLIC HEALTH RELEVANCE: Fe deficiency is the most common nutritional deficiency on earth, with health consequences that include anemia, delayed growth and development, abnormal motor and cognitive function, decreased immune function, thermoregulatory defects, fatigue and decreased work performance. Given the common occurrence of Fe deficiency and its disproportionate affects on the health of women and children, the studies outlined in this application will provide fundamentally important information on the mechanisms by which cells adapt to Fe deficiency.