Uncovering the links between circRNA accumulation, translation and aging

揭示 circRNA 积累、翻译和衰老之间的联系

• 批准号: 9764238
• 负责人: Sebastian Kadener
• 金额: $ 67.47万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764238
• 关键词: Affect; Age; Aging; Alternative Splicing; Animals; Behavioral; Biochemical; Brain; Cardiovascular Diseases; Clinical Medicine; Code; Complement; Data; Defect; Dementia; Developed Countries; Developing Countries; Development; Disease; Distant; Down-Regulation; Exons; Gene Expression; Gene Expression Regulation; Genetic; Genetic Screening; Goals; Homeostasis; In Situ; In Vitro; Internal Ribosome Entry Site; Intervention; Knock-out; Knowledge; Life; Link; Longevity; Malignant Neoplasms; Mediating; Medical; Messenger RNA; Metabolism; Methodology; MicroRNAs; Modern Medicine; Molecular; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neurons; Organ; Pathogenesis; Pathway interactions; Phenotype; Porifera; Prevalence; Process; Protein Isoforms; Proteins; RNA; Regulation; Research; Risk Factors; Role; Starvation; Stroke; Sum; System; Time; Tissues; Translating; Translation Initiation; Translations; Untranslated RNA; Work; age effect; age related; cell type; circular RNA; cis acting element; experimental study; fly; genetic variant; in vivo; innovation; knock-down; nervous system disorder; normal aging; overexpression; pathological aging; prevent; relating to nervous system; response; spatiotemporal; transcription factor; unpublished works

Project Summary As advances in clinical and medical sciences lengthen lifespan in developed countries, it is becoming increasingly clear that aging is one of the most important risk factors for disease. The prevalence of diseases including cardiovascular disease, stroke, cancer and dementia increases dramatically in the later years of life. Interventions that prevent or postpone the effects of aging have the potential to transform modern medicine. Therefore, understanding the molecular mechanisms underlying aging is an important goal. Circular RNAs (circRNAs) are highly abundant RNAs produced by circularization of specific exons. Two of these RNAs, CDR1as and Sry, can act as miRNA sponges, but no function is known for the thousands of other circRNAs found in species across the animal kingdom. CircRNAs expression levels are not correlated with the expression of their linear isoforms, indicating a potentially widespread layer of previously unknown gene regulation. Recent work from others and us showed that circRNAs are enriched in neural tissue and accumulate with age in the brain. Moreover, unpublished work from our lab demonstrate that a subset of circRNAs produces protein and that their translation is regulated by starvation and FOXO, pathways strongly related to aging This proposal aims to unravel the interplay between aging, circRNAs translation and function. For doing so, we will utilize state of the art methodologies to: Determine the cellular substrate, temporal requirements and aging pathways involved in the life span extension provoked by downregulation of circSif, circCG31619 and circCG11319. Molecularly characterize the aging related roles of circSif, circGC31619 and circCG11319. Determine the connection between translation of circRNAs and the aging phenotypes. Determine of the connection between circRNA accumulation and function and aging globally.

项目摘要 随着临床和医学的进步延长发达国家的寿命，它 越来越清楚的是，衰老是患糖尿病最重要的风险因素之一 疾病。心血管疾病、中风、癌症等疾病的流行 而痴呆症在晚年会急剧增加。干预措施，防止 或者延缓衰老的影响有可能改变现代医学。 因此，了解衰老的分子机制是重要的 进球。 环状RNA(CircRNAs)是一种高度丰富的RNA，由环化作用产生 特定的外显子。其中两个RNA，CDR1as和Sry，可以作为miRNA海绵，但 在物种中发现的数以千计的其他CircRNA的功能尚不清楚 动物王国。CircRNAs的表达水平与 它们的线性异构体，表明可能存在一层以前未知的广泛存在的 基因调控。其他人和我们最近的研究表明，CircRNA在 神经组织，并随着年龄的增长在大脑中积累。此外，未出版的作品来自 我们的实验室证明了CircRNAs的一个子集产生蛋白质，并且它们的翻译 受饥饿和FOXO调节，这些途径与衰老密切相关 这项提议旨在解开老化、CircRNA翻译和 功能。为此，我们将利用最先进的方法：确定 生命周期中涉及的细胞底物、时间需求和衰老途径 由于CircSif、CircCG31619和CircCG11319的下调而引发的延期。 CircSif、CircGC31619和CircGC31619的衰老相关作用的分子表征 大约CG11319。确定CircRNA的翻译与衰老之间的联系 表型。CircRNA积聚与功能关系的确定 在全球范围内老龄化。