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: 9918243
• 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/9918243
• 关键词: Affect; Age; Aging; Alternative Splicing; Animals; Behavioral; Biochemical; Brain; Cardiovascular Diseases; Clinical Medicine; Code; Complement; Data; Defect; Dementia; Developed 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; RNA metabolism; 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pathological aging; prevent; relating to nervous system; response; spatiotemporal; transcription factor; unpublished works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.

项目概要 随着临床和医学科学的进步延长了发达国家的寿命 越来越明显的是，衰老是最重要的风险因素之一 疾病。心血管疾病、中风、癌症等疾病的患病率 痴呆症在晚年急剧增加。预防措施 或推迟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具有重要意义。 目标。 环状 RNA (circRNA) 是通过环化产生的高丰度 RNA 特定的外显子。其中两个 RNA，CDR1as 和 Sry，可以充当 miRNA 海绵，但是 在世界各地的物种中发现的数千种其他 circRNA 的功能尚不清楚 动物王国。 CircRNA 的表达水平与以下各项的表达不相关： 它们的线性异构体，表明以前未知的潜在广泛分布层 基因调控。其他人和我们最近的工作表明，circRNA 富含 神经组织并随着年龄的增长在大脑中积累。此外，未发表的作品来自 我们的实验室证明了 circRNA 的一个子集可以产生蛋白质，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 该提案旨在揭示衰老、circRNA 翻译和衰老之间的相互作用 功能。为此，我们将利用最先进的方法来： 生命周期中涉及的细胞基质、时间需求和衰老途径 circSif、circCG31619 和 circCG11319 的下调引起延伸。 从分子角度表征 circSif、circGC31619 和 circGC31619 与衰老相关的作用 circCG11319。确定 circRNA 翻译与衰老之间的联系 表型。确定circRNA积累与功能之间的联系 和全球老龄化。