Molecular Coordination of Iron Homeostasis by microRNAs

microRNA 对铁稳态的分子协调

基本信息

批准号：
7939530
负责人：
STEPHEN L CLARKE
金额：
$ 43.61万
依托单位：
OKLAHOMA STATE UNIVERSITY STILLWATER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2013-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7939530
关键词：
Affect Anemia Animals Applications Grants Cell physiology Chronic Disease Cognitive Computer Simulation Development Diabetes Mellitus Dietary Iron Disease Extramural Activities Foundations Future Gene Expression Gene Expression Regulation Goals Health Homeostasis Impairment In Vitro Individual Iron Iron deficiency anemia Laboratories Lead Light Liver Maintenance Malignant Neoplasms Messenger RNA Metabolism MicroRNAs Modeling Molecular Molecular Profiling Motor Nutrient Physiological Population Positioning Attribute Prevalence Proteins RNA Rattus Research Role Skeletal Muscle Solid Testing Tissues United States Work biological adaptation to stress cell growth regulation disorder prevention experience immune function impaired capacity in vivo innovation insight interdisciplinary approach iron metabolism novel protein expression public health relevance response uptake

项目摘要

DESCRIPTION (provided by applicant): Diseases of iron metabolism continue to be a major health concern in the United States. Iron deficiency remains the most common single nutrient deficiency in the US and individuals experience negative health consequences due to iron deficiency in the absence of anemia, primarily due to alterations in iron metabolism in skeletal muscle. Surprisingly little is known about the molecular mechanisms regulating iron metabolism in skeletal muscle and how alterations in this tissue affects iron homeostasis. The long-term research goal of our laboratory is to advance understanding of how iron metabolism coordinated, and how alterations in iron sensing can lead to the development or prevention of disease. There is evidence suggesting expression of genes involved in iron metabolism is regulated by ID, however, the molecular mechanisms remain poorly characterized. Only recently has the role of small regulatory RNA molecules called microRNAs (miRNAs) been identified as an important mechanism for regulating various cellular processes. Our preliminary in silico analysis of miRNA targets resulted in the identification of mRNAs encoding proteins involved in iron metabolism. Thus our primary objectives are to determine the extent to which expression of miRNAs is regulated in response to ID and to characterize the impact of miRNA expression on potential regulatory targets involved in iron metabolism. We will critically evaluate targets of differentially expressed miRNAs and examine the roles of these targets in cellular iron metabolism. The central hypothesis is that miRNA expression is regulated in response to ID and that changes in expression are associated with changes in the expression target mRNAs resulting in the homeostatic regulation of cellular iron metabolism. To test this hypothesis, this proposal encompasses two specific aims. In Aim 1 we will evaluate and characterize iron-dependent changes in miRNA expression using a weanling rat model of ID. In Aim 2 we will determine the extent to which miRNAs contribute to the regulation cellular iron metabolism through modulating the expression of proteins involved in cellular iron homeostasis. MicroRNA expression profiles in the liver and skeletal muscle will be determined using miRNA microarrays and validated using qPCR. Combining in vivo and in vitro studies, we will identify and characterize target mRNAs and determine the role of these mRNAs in iron metabolism. We will also determine the extent to which changes in miRNA expression are due to alterations in iron status versus alterations in iron sensing. The proposed research is relevant to the maintenance of optimal health in light of the prevalence ID, and by taking an interdisciplinary approach to examine the relationships between iron status and cellular metabolism, we will expand our understanding of how iron contributes to the maintenance of optimal health. PUBLIC HEALTH RELEVANCE: Iron deficiency continues to be the most common nutrient deficiency and is associated with alterations ranging from impairment in immune function, delayed cognitive development, and decreased capacity of work in skeletal muscle. The focus of this project is to examine the extent to which iron status is associated with alterations in microRNA expression that may contribute to some of the tissue-specific effects of iron deficiency. The results of this study will inform our understanding of the molecular mechanisms coordinating the cellular response to iron deficiency and may have implications in understanding alterations in iron metabolism observed in chronic diseases such as cancer and diabetes.

描述（由申请人提供）：铁代谢疾病仍然是美国的主要健康问题。缺铁仍然是美国最常见的单一营养素缺乏症，在没有贫血的情况下，个人会因缺铁而遭受负面健康后果，这主要是由于骨骼肌中铁代谢的改变。令人惊讶的是，人们对调节骨骼肌铁代谢的分子机制以及该组织的变化如何影响铁稳态知之甚少。我们实验室的长期研究目标是加深对铁代谢如何协调以及铁感应的改变如何导致疾病的发展或预防的了解。有证据表明铁代谢相关基因的表达受到 ID 的调节，然而，其分子机制仍知之甚少。直到最近，称为 microRNA (miRNA) 的小调节 RNA 分子的作用才被确定为调节各种细胞过程的重要机制。我们对 miRNA 靶标进行初步计算机分析，鉴定出编码参与铁代谢的蛋白质的 mRNA。因此，我们的主要目标是确定 miRNA 的表达在 ID 响应下受到调节的程度，并表征 miRNA 表达对涉及铁代谢的潜在调节靶标的影响。我们将严格评估差异表达 miRNA 的靶标，并检查这些靶标在细胞铁代谢中的作用。中心假设是 miRNA 表达根据 ID 进行调节，并且表达的变化与表达靶标 mRNA 的变化相关，从而导致细胞铁代谢的稳态调节。为了检验这一假设，该提案包含两个具体目标。在目标 1 中，我们将使用 ID 断奶大鼠模型来评估和表征 miRNA 表达的铁依赖性变化。在目标 2 中，我们将确定 miRNA 通过调节参与细胞铁稳态的蛋白质表达来调节细胞铁代谢的程度。将使用 miRNA 微阵列确定肝脏和骨骼肌中的 MicroRNA 表达谱，并使用 qPCR 进行验证。结合体内和体外研究，我们将鉴定和表征目标 mRNA，并确定这些 mRNA 在铁代谢中的作用。我们还将确定 miRNA 表达的变化在多大程度上是由于铁状态的变化与铁感应的变化引起的。拟议的研究与 ID 患病率维持最佳健康相关，通过采用跨学科方法来研究铁状态与细胞代谢之间的关系，我们将扩大对铁如何有助于维持最佳健康的理解。公共健康相关性：缺铁仍然是最常见的营养缺乏症，并与免疫功能受损、认知发育迟缓和骨骼肌工作能力下降等变化相关。该项目的重点是检查铁状态与 microRNA 表达变化的相关程度，这些变化可能导致铁缺乏的一些组织特异性影响。这项研究的结果将帮助我们了解协调细胞对铁缺乏反应的分子机制，并可能对了解癌症和糖尿病等慢性疾病中观察到的铁代谢的变化产生影响。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evaluation of candidate reference genes for quantitative real-time PCR analysis in a male rat model of dietary iron deficiency.

DOI：
10.1186/s12263-021-00698-0
发表时间：
2021-10-02
期刊：
Genes & nutrition
影响因子：
3.5
作者：
Fiddler JL;Clarke SL
通讯作者：
Clarke SL

Comparisons of the iron deficient metabolic response in rats fed either an AIN-76 or AIN-93 based diet.

喂养 AIN-76 或 AIN-93 饮食的大鼠缺铁代谢反应的比较。

DOI：
10.1186/1743-7075-9-95
发表时间：
2012
期刊：
Nutrition & metabolism
影响因子：
4.5
作者：
Davis,McKaleR;Hester,KristenK;Shawron,KristaM;Lucas,EdralinA;Smith,BrendaJ;Clarke,StephenL
通讯作者：
Clarke,StephenL

Influence of microRNA on the maintenance of human iron metabolism.