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: 7274744
• 负责人: Scott G Kennedy
• 金额: $ 26.69万
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7274744
• 关键词: Address; Alleles; Animal Model; Biochemical Genetics; 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：许多生物暴露于双链RNA中导致含有与触发dsRNA同源的序列的mRNA分子的降解，这是一个称为RNAi的过程。诸如秀丽隐杆线虫等模型生物中的遗传和生化分析表明，RNAi的许多机械基础都是进化保守的。 RNAi领域仍有许多基本问题待解决，包括：（1）RNAi机械的内源性生物学功能是什么； （2）像大多数生物学过程一样，RNAi在负调节下吗？我们已经进行了一个遗传筛查，以识别RNAi的负调节剂。到目前为止，这些研究已导致基因ERI-1的表征。我们的结果表明，ERI-1通过降解RNAi（siRNAS）的小RNA执行者来负调节R; nai。现在，我们已经开始表征四个其他基因，这些基因在具有ERI-1的遗传途径中起作用（称为ERI-1途径）。我们的初步数据表明，ERI-1途径蛋白与秀丽隐杆线虫类c. dicer样蛋白DCR-1在复合物中起作用，以调节siRNA稳定性。最后，我们的数据表明，新型基因调节模式需要ERI-1途径蛋白，这是我们称内源性RNAi的过程。该提案试图：（1）详细介绍ERI-1的分子功能； （2）继续我们对ERI-1途径基因的遗传分析； （3）阐明了ERI-1途径基因在秀丽隐杆线虫中小RNA的生物发生和功能中的作用。最初利用siRNA靶向致癌蛋白和病毒蛋白的最初成功引起了兴奋，最终可以利用siRNA来治疗人类疾病。在理解人类疾病的基本原理使用siRNA之前，了解小RNA的内源性生物学活性以及如何产生和调节这些小型RNA是必不可少的。