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: 10401774
• 负责人: Sebastian Kadener
• 金额: $ 66.68万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401774
• 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pathological aging; prevent; relating to nervous system; response; spatiotemporal; transcription factor; unpublished works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.

项目摘要 随着临床和医学科学的进步延长了发达国家的寿命， 越来越清楚的是，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 老年痴呆症的发病率在晚年会急剧上升。预防措施 或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一个重要的 目标. 环状RNA（circRNA）是通过环化RNA而产生的高度丰富的RNA。 特定外显子。其中两种RNA，CDR1as和Sry，可以作为miRNA海绵， 对于在不同物种中发现的数千种其他circRNA， 动物王国CircRNA的表达水平与以下基因的表达不相关： 它们的线性异构体，表明一个潜在的广泛的层，以前未知的 基因调控我们和其他人的最新研究表明，circRNA富集在 随着年龄的增长，神经组织中的蛋白质会在大脑中积累。此外，未出版的作品 我们的实验室证明，一个circRNA的子集产生蛋白质， 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 功能为此，我们将利用最先进的方法来： 细胞基质、时间要求和寿命中涉及的衰老途径 通过下调circSif、circCG 31619和circCG 11319引起的延伸。 分子表征circSif、circGC 31619和 circCG 11319.确定circRNA的翻译与衰老之间的联系 表型CircRNA积累与功能之间关系的确定 和全球老龄化。

项目成果

The small RNA landscape is stable with age and resistant to loss of dFOXO signaling in Drosophila.

• DOI: 10.1371/journal.pone.0273590
• 发表时间: 2022
• 期刊: PloS one
• 影响因子: 3.7

Artificially stimulating retrotransposon activity increases mortality and accelerates a subset of aging phenotypes in Drosophila.

• DOI: 10.7554/elife.80169
• 发表时间: 2022-08-18
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Rigal, Joyce;Anduaga, Ane Martin;Bitman, Elena;Rivellese, Emma;Kadener, Sebastian;Marr, Michael T.
• 通讯作者: Marr, Michael T.

SRCP: a comprehensive pipeline for accurate annotation and quantification of circRNAs.

• DOI: 10.1186/s13059-021-02497-7
• 发表时间: 2021-09-23
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Rabin A;Zaffagni M;Ashwal-Fluss R;Patop IL;Jajoo A;Shenzis S;Carmel L;Kadener S
• 通讯作者: Kadener S

Best practice standards for circular RNA research.

• DOI: 10.1038/s41592-022-01487-2
• 发表时间: 2022-10
• 期刊: NATURE METHODS
• 影响因子: 48
• 作者: Nielsen, Anne F.;Bindereif, Albrecht;Bozzoni, Irene;Hanan, Mor;Hansen, Thomas B.;Irimia, Manuel;Kadener, Sebastian;Kristensen, Lasse S.;Legnini, Ivano;Morlando, Mariangela;Jarlstad Olesen, Morten T.;Pasterkamp, R. Jeroen;Preibisch, Stephan;Rajewsky, Nikolaus;Suenkel, Christin;Kjems, Jorgen
• 通讯作者: Kjems, Jorgen

A Parkinson's disease CircRNAs Resource reveals a link between circSLC8A1 and oxidative stress.

• DOI: 10.15252/emmm.201911942
• 发表时间: 2020-09-07
• 期刊: EMBO molecular medicine
• 影响因子: 11.1
• 作者: Hanan M;Simchovitz A;Yayon N;Vaknine S;Cohen-Fultheim R;Karmon M;Madrer N;Rohrlich TM;Maman M;Bennett ER;Greenberg DS;Meshorer E;Levanon EY;Soreq H;Kadener S
• 通讯作者: Kadener S