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） 摘要：RNA 干扰 (RNAi) 在多种生物体中提供针对外源核酸（例如病毒和转座子）的防御。对病毒或转座子序列反义的短干扰 RNA (siRNA) 的产生是 RNAi 反应的标志。在线虫中发现内源性反义 siRNA (endo-siRNA) 与数千个蛋白质编码序列相匹配，并在果蝇和哺乳动物中鉴定出类似分子，这对它们的功能提出了疑问。我们最近对秀丽隐杆线虫RNAi途径突变体中失调基因的微阵列分析揭示了RNAi成分和内源短RNA优先靶向那些失活有利于抗逆性和延长寿命的基因，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短RNA池受到自然选择的影响。因此，群体中 siRNA 的组成会根据环境变化进行调整，以达到最大的适应性。该项目的目标是测试上述模型。我们将选择对特定环境条件有抵抗力的线虫种群，并测试这些种群是否积累了与非常特定基因反义的内切siRNA，这些基因的失活允许在测试条件下生存。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，对杀线虫药物伊维菌素和左旋咪唑的生存自然选择将用于产生由于基于表观遗传内切siRNA的特定基因失活而对药物产生抗药性的线虫菌株。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性突破。基于表观遗传RNAi的机制不太可能仅限于低等生物体，并且可能参与恶性肿瘤的免疫逃逸和耐药性以及细胞进化以逃避治疗药物作用的其他情况。 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。如果我们确认线虫中的短RNA分子的组成被选择以在特定条件下最大化生存，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抵抗氧化应激能力的神经元细胞。