权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mitochondrial RNA defense pathways in the oocyte

卵母细胞中的线粒体 RNA 防御途径

基本信息

批准号：
10335216
负责人：
LANE K. CHRISTENSON
金额：
$ 29.05万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-25 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10335216
关键词：
ADAR1 Affect Aging Apoptosis Biological Assay Breeding Calcium Cell Death Cell physiology Code Competence Data Defect Development Double-Stranded RNA Embryonic Development Enzymes Fertility Functional disorder Genes Genetic Transcription Genetic Translation Health Homeostasis Human Hyperactivity Lead Life Link Longevity Macaca Macaca mulatta Mammals Maternal Age Maternal Messenger RNA Mediating Messenger RNA Mitochondria Mitochondrial RNA Mus Oocytes Output Oxidation-Reduction Pathway interactions Patients Play Population Post-Transcriptional Regulation Procedures Process Production RNA RNA Editing RNA Helicase Reactive Oxygen Species Regulation Research Retroelements Role Signal Transduction Signaling Protein Somatic Cell Structure System Testing Time Tretinoin Untranslated Regions Viral Woman Work adenosine deaminase advanced maternal age age related female fertility improved infertility treatment insight mitochondrial dysfunction novel oocyte quality preimplantation prevent protein activation protein expression recruit reproductive response sensor success transcriptome

项目摘要

Abstract Maternal aging has dramatic effects on the oocyte quality and competence, and it is well known that mitochondrial function plays important roles in oocyte health. Post-transcriptional gene regulation within the oocyte is also essential for its normal development and function. In somatic cells, mitochondria are key effectors of post-transcriptional gene regulation, where RNA sensors located on the mitochondria react in response to double stranded RNA (dsRNA) to invoke the mitochondrial RNA defense pathway. The role of the mitochondrial defense pathway, which includes RNA-editing and RNA sensing is unknown in the oocyte, even though the oocyte has an abundance of dsRNA within it. Here we provide preliminary data demonstrating an abundance of RNA edits in mouse and human oocytes, the expression of `adenosine deaminase acting on RNA' (ADAR), as well as downstream components of the RNA sensing pathway in mouse and human oocytes. Most importantly, we show that inhibition of ADAR RNA editing in oocytes results in increased accumulation of reactive oxygen species (ROS), thus implicating RNA editing as a regulator of mitochondrial function and possibly oocyte quality. Lastly, data from reproductively old mice indicate that the genes involved in RNA editing (ADAR1) and RNA sensing (p32) are decreased in oocytes, thus potentially leading to aberrant activation of mitochondrial RNA-dependent defense pathway. We propose that oocyte mitochondria are key effectors of the RNA editing and RNA sensing mechanisms within oocytes, under conditions such as aging, hyper-activity of mitochondrial RNA defense may increase ROS accumulation and ultimately impact oocyte quality. The central hypothesis we intend to test in this proposal is that the mitochondrial RNA defense pathway is a critical regulator of oocyte competence/quality. To test the central hypothesis, Specific Aim 1 will identify the specific oocyte RNA edits occurring in three species of mammalian oocytes. Specific Aim 2 will determine the role of ADAR1 and RIG-I/MAVS in the regulation of mitochondrial function in oocytes using state-of-the-art mitochondrial functional assays and assess the impact on oocyte quality/developmental potential. Specific Aim 3 will examine how advanced reproductive age impacts mitochondrial RNA sensing pathways in both mouse and human oocytes. Ultimately, this work may provide a mechanistic link (dsRNA defense pathway) that can explain the known mitochondrial dysfunction associated with oocytes from reproductively old mice and older IVF patients.

摘要