Biogenesis and Function of Regulatory RNAs

项目摘要 在过去的二十年中，成千上万的非编码RNA（ncRNA）被发现具有潜在的生物学活性， 基因表达的调节器。在这一组中，microRNAs（miRNAs）已成为必不可少的 转录后基因调控的介质，以及特定miRNA途径的缺陷， 与许多人类疾病有关。虽然对miRNAs如何表达和 功能已经实现，关于miRNA生物发生调控的突出问题， 体内靶标识别仍有待解决。秀丽隐杆蠕虫被证明是一种 这是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，以及强大的 计算管道使人们对miRNA的表达和靶向有了新的认识， 一种发育中的动物。利用和进一步创新这些资源和方法， 这项研究将有助于更好地了解miRNAs如何在体内找到和调节靶点。 动物在理想和紧张的条件下。有了一组确定的与miRNA结合的靶点 复杂的体内，功能，基础上的不同机制部署，以调节他们将是 推导许多ncRNA的鉴定，包括miRNA和长非编码RNA （lncRNA）的表达。秀丽线虫为发现新的 调节基因表达以应对这种压力。发现miRNA通路起着重要作用， 在热休克恢复过程中的关键作用，强调了这一未充分探索阶段的热的重要性 休克反应目前的研究主要集中在阐明特异性miRNAs的表达是如何影响 而lncRNA受热休克的调节，反过来，这些ncRNA如何发挥作用，以保护 生物在这种压力下在接下来的五年里，这些研究有可能揭示新的 ncRNA在热休克反应中的作用，并为研究ncRNA的影响奠定了基础。 生物体对其他压力的反应途径，包括疾病状态。远景目标 这项研究计划的目的是为ncRNA如何控制基因表达提供新的见解。 在一个完整的有机体中变化的条件。此外，从这些研究中获得的知识 对基于RNA的治疗药物的设计和利用产生重大影响的潜力 人类疾病。

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.