Metal Homeostasis in Yeast

铁（Fe）是一种必需元素，作为多种酶和蛋白质的生化辅助因子，在氧运输、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他关键生理过程中起作用。缺铁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。虽然铁缺乏会导致严重的健康后果，但对铁缺乏严重程度的分级反应的详细分子机制尚不清楚。本提案描述了研究途径，以了解真核细胞响应和适应铁缺乏的基本机制。第一个具体目标概述了实验，以破译酵母Cth1和Cth2蛋白在铁缺乏时降解mrna的差异机制，从而导致细胞代谢适应，使细胞能够应对铁可用性降低。第二个特定目标描述了实验，以了解Cth1和Cth2蛋白的表达如何在铁缺乏的情况下进行精细的微调，这种调节在铁稳态方面的生理重要性及其与细胞周期进程变化的潜在联系。鉴于铁缺乏的普遍发生及其对妇女和儿童健康的不成比例的影响，本应用程序中概述的研究将为细胞对铁缺乏的稳态反应机制提供基本的重要信息。公共卫生相关性：缺铁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。鉴于铁缺乏的普遍发生及其对妇女和儿童健康的不成比例的影响，本应用程序中概述的研究将为细胞适应铁缺乏的机制提供根本重要的信息。

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.