Cellular double-stranded RNA as a signal of stress, immunity, and aging.

细胞双链 RNA 作为压力、免疫和衰老的信号。

• 批准号: 8331579
• 负责人: Brenda L. Bass
• 金额: $ 74.73万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8331579
• 关键词: Aging; Aging-Related Process; Animal Model; Animals; Autoimmunity; Binding; Binding Proteins; Caenorhabditis elegans; Cells; Characteristics; Clinical; Detection; Diagnosis; Diagnostic; Disease; Double-Stranded RNA; Engineering; Gene Expression; Genome; Immunity; Knowledge; Longevity; Mammalian Cell; Mammals; Metabolic; Molecular Profiling; Monitor; Pathway interactions; Phenotype; Reagent; Research; Signal Transduction; Signaling Molecule; Source; Staging; Stress; Techniques; Testing; Viral; Virus Diseases; abstracting; computerized data processing; ds RNA-Binding Proteins; normal aging; overexpression; pathogen; public health relevance; research study; response

DESCRIPTION Abstract: In mammals, viral double-stranded RNA (dsRNA) triggers a response to pathogen by binding to host dsRNA binding proteins (dsRBPs). Increasingly, dsRBPs are also associated with diseased states, where a viral infection is not apparent, and the source of the dsRNA is unclear. The proposed research will explore the hypothesis that dsRNA transcribed from an animal's own genome is involved. In this model, an animal would have a characteristic pool of cellular dsRNA that would reflect metabolic state. Rapid and transient changes in dsRNA levels might occur during stress, or disease, while gradual changes during the lifetime of an animal would be part of the normal aging process. Studies to test the hypothesis will use the model organism C. elegans, as well as mammalian cells. Animals or cells will be engineered to overexpress dsRNA to test for a direct connection between levels of cellular dsRNA and the gene expression profiles and phenotypes associated with stress and aging. Sensitive high-throughput sequencing techniques will be used to identify the endogenous cellular dsRNA that serves to signal these processes. Identified cellular dsRNA and dsRBPs will be monitored for levels during stress or aging. Reagents for research and clinical purposes will be developed for the easy detection of dsRNA and to inhibit binding of dsRNAs to their target dsRBPs. The proposed experiments may uncover a previously unrecognized network of cellular dsRNA signaling molecules responsible for triggering pathways implicated in stress, autoimmunity and longevity, and set the stage for treatment and diagnosis of associated disease. Public Health Relevance: The proposed research may reveal that the causative agent in many diseased states is double-stranded RNA encoded by an animal's own genome. This knowledge would promote a huge shift in current paradigms and redirect research in ways that would accelerate progress in understanding disease and aging, and spur the search for diagnostic re

描述 摘要： 在哺乳动物中，病毒双链RNA(DsRNA)通过与宿主dsRNA结合蛋白(DsRBPs)结合来触发对病原体的反应。DsRBPs也越来越多地与疾病状态有关，在这些状态下，病毒感染不明显，dsRNA的来源也不清楚。这项拟议的研究将探索这样一种假设，即从动物自身基因组转录的dsRNA参与其中。在这个模型中，动物会有一个反映新陈代谢状态的细胞dsRNA的特征池。DsRNA水平的快速和短暂变化可能发生在应激或疾病期间，而动物一生中的逐渐变化将是正常衰老过程的一部分。检验这一假说的研究将使用模式生物秀丽线虫和哺乳动物细胞。动物或细胞将被改造成过表达dsRNA，以测试细胞dsRNA水平与压力和衰老相关的基因表达谱和表型之间的直接联系。敏感的高通量测序技术将被用来识别起到这些过程信号作用的内源性细胞dsRNA。确定的细胞dsRNA和dsRBPs将被监测应激或衰老期间的水平。将开发用于研究和临床目的的试剂，以便于检测dsRNA并抑制dsRNA与其目标dsRBPs的结合。拟议中的实验可能会发现一个以前未被识别的细胞dsRNA信号分子网络，该网络负责触发与应激、自身免疫和长寿有关的途径，并为相关疾病的治疗和诊断奠定基础。 公共卫生相关性： 这项拟议的研究可能会揭示，在许多疾病状态下，病原体是由动物自己的基因组编码的双链RNA。这一知识将推动当前范式的巨大转变，并以加速了解疾病和衰老的进步的方式重新引导研究方向，并刺激对诊断研究的探索