Investigating the Potential of Endogenous RNAi in Mediating Adaptation to Environ

研究内源性 RNAi 介导环境适应的潜力

• 批准号: 7840683
• 负责人: Alla Grishok
• 金额: $ 241.33万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7840683
• 关键词: Basic Science; Caenorhabditis elegans; Cells; Characteristics; Code; Drosophila genus; Drug resistance; Environment; Epigenetic Process; Generations; Genes; Goals; Immune; Ivermectin; Levamisole; Longevity; Lower Organism; Malignant Neoplasms; Mammals; Mediating; Microarray Analysis; Modeling; Natural Selections; Nematoda; Neurons; Nucleic Acids; Organism; Oxidative Stress; Peptide Initiation Factors; Pharmaceutical Preparations; Population; Production; Proteins; RNA; RNA Interference; RNA Interference Pathway; Resistance; Small Interfering RNA; Stress; Testing; Therapeutic Agents; Viral; Virus; abstracting; base; environmental change; fitness; mutant; public health relevance; research study; response; translation factor

DESCRIPTION (Provided by the applicant) Abstract: RNA interference (RNAi) provides defense against exogenous nucleic acids, such as viruses and transposons, in diverse organisms. The production of short interfering RNAs (siRNAs) antisense to the viral or transposon sequences is a hallmark of the RNAi response. The discovery of the endogenous antisense siRNAs (endo-siRNAs) matching thousands of protein coding sequences in C. elegans and identification of similar molecules in Drosophila and mammals poses a question about their function. Our recent microarray analysis of genes misregulated in the RNAi pathway mutants in C. elegans revealed preferential targeting by the RNAi components and endogenous short RNAs of genes whose inactivation is beneficial for stress resistance and lifespan extension, such as genes encoding translation factors. We propose that pools of endogenous short RNAs in C. elegans are subject to natural selection. Therefore, the composition of siRNAs in populations is adjusted in response to the environmental changes to achieve maximum fitness. The goal of this project is to test the above model. We will select populations of C. elegans resistant to specific environmental conditions and test these populations for the accumulation of endosiRNAs antisense to very specific genes whose inactivation allows survival under the tested condition. We already established a correlation between thermotolerance and accumulation of endo-siRNAs specific to translation initiation factors. In addition, natural selection for survival on the nematocidal drugs ivermectin and levamisole will be used to generate C. elegans strains resistant to drugs due to epigenetic endo-siRNA-based inactivation of specific genes. Proving the existence of a siRNA-based epigenetic natural selection would represent a fundamental breakthrough in basic science. Epigenetic RNAi-based mechanisms are not likely to be limited to lower organisms and may be involved in the immune escape and drug-resistance of malignant tumors and in other cases when cells evolve to escape the action of therapeutic agents. Public Health Relevance: This project is focused on revealing new mechanisms used by organisms for the adaptation to environment. If we confirm that composition of short RNA molecules in the nematode C. elegans is selected to maximize survival under specific conditions, this will open the doors for "natural selection" experiments aimed at generation of cells with specific characteristics. For example, neuronal cells with enhanced ability to resist oxidative stress could be generated.

描述（由申请人提供） 翻译后摘要：RNA干扰（RNAi）提供防御外源核酸，如病毒和转座子，在不同的生物。与病毒或转座子序列反义的短干扰RNA（siRNA）的产生是RNAi应答的标志。内源性反义siRNA（endo-siRNAs）的发现与C.在果蝇和哺乳动物中鉴定出类似的分子，提出了关于它们功能的问题。我们最近的基因芯片分析的RNAi途径突变体在C。elegans揭示了RNAi组分和内源性短RNA对失活的基因的优先靶向作用，这些基因的失活有益于胁迫抗性和寿命延长，例如编码翻译因子的基因。我们认为C.秀丽线虫是自然选择的对象因此，种群中siRNA的组成会根据环境变化进行调整，以达到最大的适应性。本项目的目标是测试上述模型。我们将选择C. elegans对特定环境条件的抗性，并测试这些群体中与非常特异的基因反义的内切siRNA的积累，所述基因的失活允许在测试条件下存活。我们已经建立了耐热性和翻译起始因子特异性内切siRNA积累之间的相关性。此外，将利用杀线虫药物伊维菌素和左旋咪唑的生存自然选择来产生C。由于特定基因的基于表观遗传内siRNA的失活，线虫菌株对药物具有抗性。证明基于siRNA的表观遗传自然选择的存在将代表基础科学的根本突破。基于表观遗传RNAi的机制不太可能局限于低等生物，并且可能参与恶性肿瘤的免疫逃逸和耐药性，以及在细胞进化以逃避治疗剂作用的其他情况下。 公共卫生相关性：该项目的重点是揭示生物体适应环境的新机制。如果我们证实线虫C.选择线虫在特定条件下最大限度地存活，这将为旨在产生具有特定特征的细胞的“自然选择”实验打开大门。例如，可以产生具有增强的抗氧化应激能力的神经元细胞。