Biogenesis and Function of Regulatory RNAs

项目概要 在过去的十年中，数千种非编码 RNA (ncRNA) 被发现具有潜在的潜力。 基因表达的调节因子。在这一群体中，microRNA (miRNA) 已成为必不可少的 转录后基因调控的介质以及特定 miRNA 通路的缺陷 与许多人类疾病有关。虽然对 miRNA 的表达方式有基本的了解， 功能已经实现，关于 miRNA 生物发生和调控的悬而未决的问题 目标识别仍有待解决。特别是，miRNA 通路已被证明发挥着重要作用。 在不同的应激反应中发挥着重要作用，但控制 miRNA 表达和 对非理想条件下的活动知之甚少。秀丽隐杆线虫有 被证明是在有机体水平上研究 miRNA 生物学的有利模型。的 开发灵敏的生化方法、独特的蠕虫菌株和强大的计算能力 pipelines 为 miRNA 表达和靶向提供了新的见解 发育中的动物。这些方法现在被用来了解 miRNA 如何发挥作用 机体对热应激的反应。此外，数十种新型长非编码 RNA （lncRNA）被发现是由热休克诱导的，并且其中之一已被证明可以 促进在这种压力下的生存。因此，多种 ncRNA 途径可能有助于 在这种应激条件下生存所需的基因表达的变化。拟议的研究是 重点阐明特定 miRNA 和 lncRNA 的表达如何受热调节 以及这些 ncRNA 在这种压力下如何发挥作用来保护生物体。超过 未来 5 年，这些研究有可能揭示 ncRNA 在热反应中的新作用 震惊并为研究 ncRNA 通路对生物体反应的影响奠定基础 其他压力，包括疾病状态。旨在了解 3' 聚 (A) 尾部如何作用的工作 信使 RNA (mRNA) 有助于 miRNA 复合物的结合和调节，从而导致 令人惊讶的发现是，短聚腺苷酸尾通常与高表达基因相关 体细胞。因此，一个新的研究方向解决了以前未认识到的复杂性 Poly(A) 尾长控制及其与基因表达调控的关系。长期目标 该研究计划的目的是为 ncRNA 和调控元件如何在 mRNA，例如聚腺苷酸尾，在不同条件下控制生物体基因表达。 此外，从这些研究中获得的知识有可能对 设计和利用基于RNA的疗法来治疗人类疾病。

PROJECT SUMMARY Over the past decade, 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 remain to be solved. In particular, the miRNA pathway has been shown to play an important role in diverse stress responses, but the mechanisms that control miRNA expression and activity under non-ideal conditions are poorly understood. 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 and robust computational pipelines has enabled novel insights into miRNA expression and targeting in the context of a developing animal. These approaches are now being utilized to understand how miRNAs contribute to the organismal response to heat stress. Additionally, dozens of novel long non-coding RNAs (lncRNAs) were found to be induced by heat shock and, already, one of them has been shown to promote survival during this stress. Thus, multiple ncRNA pathways potentially contribute to the changes in gene expression needed to survive this stress condition. The proposed 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 5 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. Work aimed at understanding how the 3' poly(A) tail on messenger RNAs (mRNAs) contributes to binding and regulation by the miRNA complex led to the surprising discovery that short poly(A) tails are commonly associated with highly expressed genes in somatic cells. Thus, a new research direction addresses previously unrecognized complexities in poly(A) tail length control and its relationship to the regulation of gene expression. The long-term goal of this research program is to contribute new insights into how ncRNAs and regulatory elements in mRNAs, such as poly(A) tails, control organismal gene expression under varied conditions. 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.