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Translational control of selenoprotein synthesis

硒蛋白合成的翻译控制

基本信息

批准号：
8666645
负责人：
MICHAEL T HOWARD
金额：
$ 14.75万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-27 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8666645
关键词：
Address Affect Amino Acids Anticodon Biochemical Biochemical Pathway Biological Assay Biology Brain Codon Nucleotides Data Diabetes Mellitus Dietary Selenium Dietary intake Disease Elements Genes Genetic Transcription Goals Health Housekeeping Housing Human In Vitro Intake Kidney Knowledge Lead Length Link Liver Male Infertility Malignant Neoplasms Mammals Measures Messenger RNA Methodology Methods Methylation Modification Molecular Mus Muscle Mutagenesis Myopathy Neurodegenerative Disorders Oryctolagus cuniculus Physiological Positioning Attribute Predisposition Process Production Protein Isoforms Proteins Reaction Regulation Reporter Reporting Resistance Reticulocytes Ribosomes Selenium Selenocysteine Site Stress System Testing Thyroid Hormones Tissues Transfer RNA Transgenic Mice Transgenic Organisms Translating Translations Variant Virus Diseases abstracting base cis acting element density dietary supplements high risk immune function improved in vivo insight methyl group new technology overexpression programs research study selenium deficiency selenocysteine-tRNA selenocysteinyl-tRNA selenoprotein sensor transcriptome sequencing translation assay

项目摘要

DESCRIPTION (provided by applicant): Abstract: The environmental element selenium (Se) is essential for human health in small amounts, but toxic at high levels. There is strong evidence that even small changes in Se status have multi-faceted effects on human health which include altered immune function and susceptibility to viral infections, biochemical stresses, cancer, and even diabetes. Many of the beneficial effects of Se can be attributed to selenoproteins; proteins containing Se in the form of the 21st amino acid selenocysteine (Sec). The diversity of substrates and biochemical pathways that selenoproteins act upon likely explains the multiple health effects associated with Se intake. Se is incorporated into selenoproteins co-translationally by redefinition of a UGA codon to encode Sec. In mammals UGA-Sec codons are decoded by two isoforms of Sec-tRNA[Ser]Sec differing only by the presence or absence of a methyl group at the anticodon position Um34. Methylation of this residue in vivo is dependent upon Se status. The unmethylated isoform predominates when Se is deficient, whereas the opposite is true under Se sufficiency. Previous studies suggest that the house-keeping selenoproteins can incorporate Sec using either isoform, whereas the stress-related selenoproteins prefer the methylated form of Sec-tRNA[Ser]Sec. We hypothesize that Se-dependent changes in the ratio of unmethylated to methylated Sec-tRNA[Ser]Sec provides the direct link between Se availability and gene-specific regulation of selenoprotein production. To test this hypothesis and further explore translational control of selenoprotein expression in vivo (Aim 1), we will develop and validate ribosome profiling as a methodology to quantify ribosome position and density on selenoprotein mRNAs in tissues from mice raised on Se deficient, adequate or supplemented diets. In addition, we will examine ribosome distribution in tissues from transgenic mice overexpressing the unmethylated isoform of Sec-tRNA[Ser]Sec. In Aim 2, we will establish an in vitro tRNA-defined rabbit reticulocyte translation system programmed with the methylated or unmethylated isoforms of Sec-tRNA[Ser]Sec to directly test Sec incorporation efficiency during translation of a subset of the house-keeping and stress-related selenoprotein mRNAs and identify the cis-acting elements involved. The results from experiments proposed here promise to establish a new methodology to examine selenoprotein synthesis and to further elucidate the mechanism of Se-dependent regulation of selenoprotein expression, a finding of direct relevance to the health effects of Se.

描述（由申请人提供）：