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（申请人提供） 摘要：RNA干扰（RNAI）提供了不同生物体中的外源核酸（例如病毒和转座子）的防御。对病毒或转座子序列的简短干扰RNA（siRNA）反义的产生是RNAi响应的标志。在秀丽隐杆线虫中与数千种蛋白质编码序列相匹配的内源性反义siRNA（内源性siRNA）的发现，果蝇和哺乳动物中相似分子的鉴定提出了一个问题。我们最近对秀丽隐杆线虫中RNAi途径突变体中的基因的微阵列分析揭示了RNAi成分和基因内源性短RNA的优先靶向，这些基因的灭活对压力抗性和寿命扩展有益，例如编码翻译因子的基因。我们建议秀丽隐杆线虫中的内源性短RNA池进行自然选择。因此，根据环境变化以实现最大的适应性，对种群中siRNA的组成进行了调整。该项目的目的是测试上述模型。我们将选择具有特定环境条件的秀丽隐杆线虫的种群，并测试这些种群，以积累内质反义与非常特定的基因，这些基因的失活允许在测试条件下生存。我们已经建立了与翻译起始因子特有的内核的耐热性和积累之间的相关性。此外，由于表观遗传性内核基于特定基因的灭活而导致的秀丽隐杆线虫菌株对杀虫剂菌株的自然选择将用于产生对秀丽隐杆菌菌株的抗药性。证明基于siRNA的表观遗传自然选择的存在将代表基础科学中的基本突破。基于表观遗传学的RNAi机制不可能限于较低的生物体，并且可能参与恶性肿瘤的免疫逃生和抗药性，而在其他情况下，当细胞发展以逃避治疗剂的作用时。 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。如果我们确认选择了线虫C.秀丽隐杆线虫中短的RNA分子的组成以在特定条件下最大化生存，这将打开旨在生成具有特定特征细胞的“自然选择”实验的门。例如，可以产生具有抗氧化应激能力增强的神经元细胞。