Investigating the role of cytosolic mitochondrial double-stranded RNA in cellular senescence and aging

研究细胞质线粒体双链 RNA 在细胞衰老中的作用

• 批准号: 10721145
• 负责人: Joao Passos
• 金额: $ 45.59万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721145
• 关键词: Aging; BAX gene; Biological; Cell Aging; Cell Cycle Arrest; Cells; Chronic; Clinical Treatment; Cytosol; DNA; Data; Development; Disease; Double-Stranded RNA; Drug Targeting; Functional disorder; Genes; Genetic; Genetic Transcription; Goals; Impairment; Inflammation; Inflammatory; Inflammatory Response; Intervention; Knowledge; Link; Mediating; Minority; Mitochondria; Mitochondrial DNA; Mitochondrial RNA; Mus; Nuclear; Pathway interactions; Phenotype; Process; RNA; Regulation; Role; Stimulator of Interferon Genes; Structure; TLR3 gene; Tissues; Transcript; Transfection; Tumor Suppression; Work; age related; drug development; efficacy testing; experimental study; healthspan; healthy aging; immunogenic; improved; in vivo; innovation; interest; major outer membrane protein; mitochondrial dysfunction; novel; novel therapeutics; pharmacologic; preservation; senescence; sensor; therapeutic target; tissue degeneration

PROJECT SUMMARY/ABSTRACT This application investigates the relationship between mitochondrial RNA, inflammation, senescence, and aging. Cellular senescence is a well-established driver of tissue and organismal aging, a process thought to be partly mediated via the induction of a chronic Senescence-associated secretory phenotype (SASP). Consequently, there is great interest in selectively targeting senescent cells as a strategy to promote healthy aging. Our work has demonstrated that mitochondrial dysfunction is a hallmark of cellular senescence and a driver of the SASP and that by targeting them we may be able to suppress the detrimental SASP known to contribute to aging. Mitochondrial double-stranded RNA (mtdsRNA) when present in the cytosol is known to be especially immunogenic and trigger an inflammatory response. We observed that senescent cells contain increased levels of cytosolic mtdsRNA together with increased expression of RNA sensors. Furthermore, we found that transfection of cells with mtdsRNA triggers an inflammatory response and inhibition of mitochondrial DNA transcription in senescent cells, decreases the SASP. Finally, we observed that mtdsRNA requires the cytosolic DNA sensor cGAS to induce inflammation suggesting an interplay between RNA and DNA sensing pathways in the process. This led us to hypothesize that cytosolic mdsRNA plays a role in the regulation of the SASP and may be a novel target for interventions to improve healthspan during aging. In this project, we will dissect the mechanisms by which mtdsRNA increases in the cytosol of senescent cells as well as investigate if activation of RNA sensing pathways contributes to the SASP. Additionally, we will explore the mechanisms mediating the interplay between mitochondrial DNA and RNA in the development of the SASP. Our ultimate goal is to identify new interventions that target senescent cells to alleviate age-related dysfunction.

项目摘要/摘要 该应用研究了线粒体RNA，炎症，衰老和衰老之间的关系。 细胞衰老是组织和有机衰老的良好驱动力，这一过程被认为是部分的 通过诱导慢性衰老相关分泌表型（SASP）介导。最后， 有选择地将衰老细胞作为促进健康衰老的策略引起了极大的兴趣。我们的工作 已经证明线粒体功能障碍是细胞衰老的标志，也是SASP的驱动力 通过针对它们，我们可能能够抑制已知会导致衰老的有害SASP。 线粒体双链RNA（mTDSRNA）当时存在于细胞质中时 免疫原性并触发炎症反应。我们观察到衰老细胞含有增加的水平 胞质mtDSRNA以及RNA传感器的表达增加。此外，我们发现 用mTDSRNA转染细胞会触发炎症反应和抑制线粒体DNA 衰老细胞中的转录减少SASP。最后，我们观察到mtDSRNA需要胞质 DNA传感器CGA诱导炎症，表明RNA和DNA感应途径之间的相互作用 过程。这使我们假设胞质mdsrNA在SASP的调节中起作用 可能是改善衰老期间健康状况的新颖目标。 在这个项目中，我们将剖析mtDSRNA在衰老细胞的细胞质中增加的机制 并研究RNA感应途径的激活是否有助于SASP。此外，我们将探索 SASP开发中线粒体DNA与RNA之间的相互作用的机制。 我们的最终目标是确定靶向衰老细胞以减轻与年龄相关的功能障碍的新干预措施。