Endogenous Circular RNAs and the Control of Expression of Aging-related Genes

内源性环状RNA与衰老相关基因表达的控制

基本信息

批准号：
8447297
负责人：
William R Jeck
金额：
$ 3.3万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-16 至 2015-09-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8447297
关键词：
9p21 Age Aging Atherosclerosis Base Sequence Binding Biochemical Biological Process CDKN2A gene Caucasians Caucasoid Race Cell Aging Cell Cycle Regulation Cell Line Cerebrovascular Disorders Chromatin Chromosomes Chromosomes, Human, Pair 9 Code Complex Coronary Arteriosclerosis Data Set Detection Diabetes Mellitus Digestion Disease Epigenetic Process Exonuclease Functional RNA Gene Expression Profile Genes Genetic Genetic Polymorphism Genome Genomics Haplotypes Heart Diseases Hepatitis Human Genome Individual Ischemic Stroke Lead Malignant Neoplasms Messenger RNA Methods Modeling Mus Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Organ PRC1 Protein Peripheral Blood Lymphocyte Play Polycomb Population Production Proteins Publishing RNA RNA Binding RNA Helicase RNA Sequences RNA Splicing Repression Research Reverse Transcription Ribosomal RNA Risk Role Single Nucleotide Polymorphism Testing Transcript Tumor Suppressor Proteins Variant Virus Work age related base cDNA Library cell type chromatin immunoprecipitation circular RNA disorder risk endometriosis frailty genome wide association study genome-wide histone modification interest member mortality next generation novel programs regenerative

项目摘要

DESCRIPTION (provided by applicant): Extensive work has established that the beneficial, anti-cancer function of the p16INK4a tumor suppressor mechanism makes counteracting negative contributions to mammalian aging. Age associated increases of p16INK4a in this model repress the proliferative and regenerative potential of some organ compartments. Though many of the findings demonstrating this counterbalancing effect of p16INK4a were observed in murine models, recent genome wide association studies (GWAS) have independently and repeatedly found associations with single nucleotide polymorphisms (SNPs) proximal to p16INK4a and numerous age-associated conditions, such as frailty, type 2 diabetes, atherosclerotic disease (including myocardial infarction, ischemic stroke, intracranial aneurism and aortic aneurism), and endometriosis. These variants are in strong linkage with haplotypes that overlap ANRIL, a long non-coding RNA of unknown biological function. We have previously demonstrated that ANRIL produces alternatively spliced mRNA and, unexpectedly, circular RNA species, and moreover that expression of some of these species correlate to GWAS identified SNPs. In this work we intend to investigate these species using genome wide and focused approaches. In aim 1 we will assess the association between previously identified polycomb group repressor complex members (SUZ12, CBX7 and MOV10) and circular ANRIL. In aim 2 we will develop and apply a method for genome wide identification of endogenous circular RNA transcripts. Together these will elucidate the role of the little studied circular RNA constituent f the mammalian transcriptome and develop our understanding of the role of important non-coding RNAs relevant to numerous diseases of aging.

描述（由申请人提供）：广泛的工作已经确定，p16INK4A抑制剂机制的有益的抗癌功能使得对哺乳动物衰老的负面贡献进行了抵消。在该模型中，P16INK4A与年龄相关的增加抑制了某些器官室的增殖和再生潜力。 Though many of the findings demonstrating this counterbalancing effect of p16INK4a were observed in murine models, recent genome wide association studies (GWAS) have independently and repeatedly found associations with single nucleotide polymorphisms (SNPs) proximal to p16INK4a and numerous age-associated conditions, such as frailty, type 2 diabetes, atherosclerotic disease (including myocardial infarction, ischemic中风，颅内动脉瘤和主动脉动脉瘤）和子宫内膜异位症。这些变体与重叠Anril的单倍型有很强的联系，而Anril是一个未知生物学功能的长期非编码RNA。我们以前已经证明，Anril会产生剪接的mRNA，并且出乎意料地是圆形RNA物种，此外，其中一些物种的表达与GWAS相关的SNP相关。在这项工作中，我们打算使用广泛和集中的方法研究这些物种。在AIM 1中，我们将评估先前鉴定的PolyComb组抑制剂复合构件（SUZ12，CBX7和MOV10）与圆形Anril之间的关联。在AIM 2中，我们将开发并采用一种基因组广泛鉴定内源性圆形RNA转录物的方法。这些将共同阐明哺乳动物转录组的较少研究的圆形RNA成分的作用，并发展我们对与多种衰老疾病有关的重要非编码RNA的作用的理解。