Regulation of Small RNAs by the eri-1 Genetic Pathway

eri-1 遗传途径对小 RNA 的调控

• 批准号: 7682845
• 负责人: Scott G Kennedy
• 金额: $ 26.68万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-20 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7682845
• 关键词: Address; Alleles; Animal Model; Biochemical; Biogenesis; Biological; Biological Process; Biology; Caenorhabditis elegans; Complex; Data; Double-Stranded RNA; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Screening; Goals; Knowledge; Mammals; Messenger RNA; Molecular; Oncogenic; Organism; Pathway interactions; Process; Proteins; RNA Interference; Regulation; Research; Resistance; Role; Sequence Homologs; Small Interfering RNA; Small RNA; System; Technology; Testing; Therapeutic; Viral Proteins; design; genetic analysis; human DICER1 protein; human disease; mRNA Transcript Degradation; mutant; novel; protein function; research study; success

Exposure of many organisms to double-stranded RNA causes the degradation of mRNA molecules containing sequences homologous to the trigger dsRNA, a process termed RNAi. Genetic and biochemical analysis in model organisms, such as C. elegans, has demonstrated that much of the mechanistic underpinnings of RNAi are evolutionary conserved. Many fundamental questions remain to be addressed in the RNAi field including: (1) What are the endogenous biological functions of the RNAi machinery; and (2) Is RNAi, like most biological processes, under negative regulation? We have undertaken a genetic screen seeking to identify negative regulators of RNAi. These studies have thus far led to the characterization of the gene eri-1. Our results suggest that ERI-1 functions to negatively regulate R;NAi by degrading the small RNA executioners of RNAi (siRNAs). We have now begun to characterize four additional genes which function in a genetic pathway with eri-1 (termed the eri-1 pathway). Our preliminary data suggests that the eri-1 pathway proteins function in a complex with the C. elegans Dicer-like protein DCR-1 to regulate siRNA stability. Finally, our data indicate that the eri-1 pathway proteins are required for a novel mode of gene regulation, a process we term endogenous RNAi. This proposal seeks to: (1) characterize the molecular function of ERI-1 in detail; (2) continue our genetic analysis of the eri-1 pathway genes; and (3) elucidate the role of the eri-1 pathway genes in the biogenesis and function of small RNAs in C. elegans. Initial successes utilizing siRNAs to target oncogenic and viral proteins have generated excitement that siRNAs may eventually be utilized to treat human disease. Understanding the endogenous biological activities of small RNAs and how these small RNAs are generated and regulated is essential prior to the rationale use of siRNAs in treating human disease.

许多生物体接触双链 RNA 会导致 mRNA 分子降解 含有与触发 dsRNA 同源的序列，这一过程称为 RNAi。遗传和 对模式生物（例如线虫）的生化分析表明，许多 RNAi 的机制基础在进化上是保守的。许多基本问题仍有待解决 RNAi领域需要解决的问题包括：（1）RNAi的内源性生物学功能是什么？ 机械; (2) RNAi 是否像大多数生物过程一样受到负调控？我们有 进行了基因筛选，试图识别 RNAi 的负调节因子。这些研究迄今为止 导致了基因 eri-1 的表征。我们的结果表明 ERI-1 具有负面作用 通过降解 RNAi (siRNA) 的小 RNA 执行子来调节 R;NAi。我们现在已经开始 描述了另外四个基因的特征，这些基因与 eri-1 一起在遗传途径中发挥作用（称为 eri-1 途径）。我们的初步数据表明 eri-1 通路蛋白与 线虫 Dicer 样蛋白 DCR-1 调节 siRNA 稳定性。最后，我们的数据表明 eri-1 途径蛋白是一种新的基因调控模式所必需的，我们将这一过程称为内源性 RNAi。该提案旨在：（1）详细表征ERI-1的分子功能； （2）继续我们的 eri-1途径基因的遗传分析； (3)阐明eri-1途径基因在 秀丽隐杆线虫中小RNA的生物发生和功能。利用 siRNA 进行靶向治疗取得初步成功 致癌蛋白和病毒蛋白引起了人们的兴奋，因为 siRNA 最终可能用于治疗 人类疾病。了解小RNA的内源生物活性以及这些小RNA如何 在合理使用 siRNA 治疗人类之前，RNA 的生成和调节至关重要 疾病。