Biogenesis and Function of Regulatory RNAs

项目总结 在过去的二十年里，数以千计的非编码RNA(NcRNAs)被发现作为潜在的 基因表达的调节者。在这一群体中，microRNAs(MiRNAs)已成为必不可少的 转录后基因调节的介体和特定miRNA途径中的缺陷 与许多人类疾病有关。虽然对miRNAs是如何表达和 功能已经实现，关于miRNA生物发生和调控的突出问题 体内靶点识别仍有待解决。秀丽隐杆线虫已被证明是一种 在生物体水平上研究miRNA生物学的有利模型。的发展。 灵敏的生化方法、独特的蠕虫菌株、广泛的基因组数据集和强大的 计算管道使人们能够对上下文中的miRNA表达和靶向有新的见解 指发育中的动物。利用和进一步创新这些资源和方法，建议 研究将有助于更好地理解miRNAs如何在活体内寻找和调节靶标 理想和压力条件下的动物。有一组由miRNA结合的有信心的靶点 在体内，为调节它们而部署的不同机制所依据的特征将是 推断出来的。识别大量的ncRNAs，包括miRNAs和长的非编码RNA (LncRNAs)，为发现新的致病机制奠定了基础 调节基因表达以应对这种压力。发现miRNA途径发挥着一种 在热休克恢复过程中的关键作用，突出了这一未被开发的热阶段的重要性 电击反应。目前的研究集中在阐明特定的miRNAs是如何表达的 而lncRNAs受热休克的调节，反过来，这些ncRNAs是如何发挥作用来保护 有机体在这种压力下。在接下来的五年里，这些研究有可能揭示小说 NcRNA在热休克反应中的作用并为研究ncRNA的影响奠定了基础 机体对包括疾病状态在内的其他应激反应的途径。长期目标 这项研究计划的目的是为ncRNAs如何控制基因表达在 在一个完整的有机体中有不同的条件。此外，从这些研究中获得的知识具有 可能对基于RNA的治疗药物的设计和使用产生重大影响 人类疾病的威胁。

PROJECT SUMMARY In the past twenty years, thousands of non-coding RNAs (ncRNAs) have been discovered as potential regulators of gene expression. Within this group, microRNAs (miRNAs) have emerged as essential mediators of post-transcriptional gene regulation, and defects in specific miRNA pathways have been linked to numerous human diseases. While a basic understanding of how miRNAs are expressed and function has been achieved, outstanding questions regarding the regulation of miRNA biogenesis and target recognition in vivo remain to be solved. Caenorhabditis elegans worms have proven to be an advantageous model to investigate miRNA biology at the organismal level. The development of sensitive biochemical methods, unique worm strains, extensive genomic datasets, and robust computational pipelines has enabled novel insights into miRNA expression and targeting in the context of a developing animal. Utilizing and further innovating these resources and methods, the proposed research will contribute to a better understanding of how miRNAs find and regulate targets within a live animal under ideal as well as stressful conditions. With a confident set of targets bound by the miRNA complex in vivo, features that underlie the different mechanisms deployed to regulate them will be deduced. The identification of numerous ncRNAs, including miRNAs and long non-coding RNAs (lncRNAs), induced by heat shock in C. elegans sets a foundation for discovering new mechanisms for regulating gene expression in response to this stress. The discovery that the miRNA pathway plays a key role during heat shock recovery, highlights the importance of this under-explored phase of the heat shock response. The current research is focused on elucidating how the expression of specific miRNAs and lncRNAs is regulated by heat shock and, in turn, how these ncRNAs function to protect the organism during this stress. Over the next five years, these studies have the potential to reveal novel roles for ncRNAs in response to heat shock and set the stage for investigating the impact of ncRNA pathways in the organismal response to other stresses, including disease states. The long-term goal of this research program is to contribute new insights into how ncRNAs control gene expression under varied conditions in an intact organism. Furthermore, knowledge gained from these studies has the potential for significant impact on the design and utilization of RNA-based therapeutics for the treatment of human disease.