Translational control of mitochondrial gene expression

线粒体基因表达的翻译控制

基本信息

批准号：
9022601
负责人：
MICHAEL F HENRY
金额：
$ 48.3万
依托单位：
ROWAN UNIVERSITY SCHOOL/OSTEOPATHIC MED
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-10 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9022601
关键词：
10 year old Affect Aging Amino Acids Animal Model Antibiotics Bacterial Genes Binding Biochemical Genetics Cells Child Complex Coupled Coupling Data Degenerative Disorder Disease Event Fermentation Functional disorder Future Gene Expression Genetic Transcription Goals Homologous Gene Human In Vitro Linezolid Malignant Neoplasms Measures Membrane Messenger RNA Mitochondria Mitochondrial Diseases Modeling Molecular Monitor Muscle Cells Mutagenesis Nuclear Organ Organism PTGS1 gene Pathway interactions Physiological Process Production Proteins Reactive Oxygen Species Regulation Research Respiration Respiratory Chain Ribosomes Structure Sum Surface System Testing Transcript Translational Activation Translations Yeast Model System Yeasts base brain cell cytochrome c oxidase innovation mitochondrial genome novel prevent public health relevance research study three dimensional structure transcription factor translation factor

项目摘要

DESCRIPTION (provided by applicant): The goal of the proposed research is to define the mechanisms of translational activation within mitochondria. Alterations in mitochondrial gene expression can compromise cellular energy production and generate reactive oxygen species that promote degenerative disease, aging, and cancer. Thus, a clearer understanding of how this system is regulated is necessary to better understand mitochondrial disease. To explore this process further, the first aim will elucidate the mechanism by which the newly discovered yeast translational activator Mam33 activates the translation of COX1, a core subunit of the cytochrome c oxidase complex. These experiments will determine 1) the region of COX1 mRNA sufficient for Mam33-dependent activation, 2) whether Mam33 directly binds the COX1 transcript, 3) if Mam33 associates with the mitochondrial ribosome, and 4) if Mam33 is rate-limiting. This information will advance our understanding of Mam33 and mitochondrial activators in general, which can be later tested with human homologues. The second aim will employ biochemical and genetic strategies to identify and characterize factors that physically interact with - or are functionally related to Mam33. These results will allow us to place Mam33 within the COX1 expression pathway and better define its translation activation mechanism. Additionally, unanticipated Mam33 activities may be revealed. The third aim is to understand the structural requirements for Mam33 activity. A mutational analysis based upon crystal structure features and amino acid conservation found in homologs from other organisms will be performed. Since both Cox1 and Mam33 are evolutionarily conserved, information gained in yeast will likely be applicable to human mitochondrial disorders. Furthermore, recent data also implicates the human homologue p32 in cancer. Thus, a better understanding of yeast Mam33 could also enhance our understanding of cancer.

描述（由申请人提供）：拟议研究的目标是确定线粒体内翻译激活的机制，线粒体基因表达的改变会损害细胞能量产生并产生促进退行性疾病、衰老和癌症的活性氧。为了更好地理解线粒体疾病，有必要更清楚地了解该系统的调节方式。为了进一步探索这一过程，首要目标是阐明新发现的酵母翻译激活剂 Mam33 激活翻译的机制。 COX1，细胞色素 c 氧化酶复合物的核心亚基，这些实验将确定 1) COX1 mRNA 的区域足以进行 Mam33 依赖性激活，2) Mam33 是否直接结合 COX1 转录物，3) Mam33 是否与线粒体核糖体结合， 4) Mam33 是否具有限速作用。该信息将增进我们对 Mam33 和线粒体激活剂的总体理解，并可在以后进行测试。第二个目标是采用生化和遗传策略来识别和表征与 Mam33 物理相互作用或功能相关的因子。这些结果将使我们能够将 Mam33 置于 COX1 表达途径中，并更好地定义其翻译激活机制。此外，可能会揭示出乎意料的 Mam33 活性，以了解 Mam33 活性的结构要求。由于 Cox1 和 Mam33 在进化上都是保守的，因此在酵母中获得的信息可能适用于人类线粒体疾病。此外，最近的数据还表明人类同源物 p32 与癌症有关。因此，更好地了解酵母 Mam33 也可以增强我们的理解。癌症。