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: 8142547
• 负责人: Brenda L. Bass
• 金额: $ 74.75万
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8142547
• 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 抽象的： 在哺乳动物中，病毒双链RNA（DSRNA）通过与宿主dsRNA结合蛋白（DSRBP）结合来触发对病原体的反应。 DSRBP越来越多地与病毒感染不明显的患病状态有关，而DSRNA的来源尚不清楚。拟议的研究将探讨从动物自己的基因组转录的dsRNA的假设。在该模型中，动物将具有反映代谢状态的细胞dsRNA的特征池。在压力或疾病期间，DSRNA水平的快速和瞬时变化可能发生，而动物一生中逐渐变化将成为正常衰老过程的一部分。测试假设的研究将使用模型有机体秀丽隐杆线虫以及哺乳动物细胞。动物或细胞将被设计为过表达DSRNA，以测试细胞DSRNA水平与与压力和衰老相关的基因表达谱和表型之间的直接连接。敏感的高通量测序技术将用于识别用于信号这些过程的内源性细胞DSRNA。在压力或衰老期间，将监测已鉴定出的细胞DSRNA和DSRBP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与目标DSRBP的结合。提出的实验可能会发现先前未知的细胞DSRNA信号传导分子网络，负责触发与压力，自身免疫性和寿命有关的途径，并为治疗和诊断相关疾病奠定了基础。 公共卫生相关性： 拟议的研究可能表明，许多患病状态的病因是由动物自己的基因组编码的双链RNA。这些知识将以当前范式的巨大转变和重定向研究，以加速理解疾病和衰老的进展，并刺激寻找诊断性的。