Molecular control of microRNA gene-regulatory activity.

项目摘要 基因表达的适当控制对于维持细胞和组织的稳态是必不可少的。改变 基因表达的调节导致许多疾病，包括癌症和神经退行性疾病。 和代谢紊乱。一个重要的基因调控层发生在转录后水平， 由一类称为microRNA（miRNAs）的小的非编码RNA协调。miRNA功能的改变 导致许多疾病，但我们缺乏关于如何控制miRNA活性的完整知识， 差异抑制靶基因。拟议的研究计划的主要目标是了解如何 miRNA活性在生物体的复杂环境中受到调节。更具体地说，我们将讨论两个 这些问题限制了我们对发育和疾病中miRNA基因调控活性的理解。 1. miRNA靶基因特异性是如何通过调控miRNA诱导的沉默复合体来建立的 （miRISC）编程与特定的miRNA链？和2.辅助miRISC蛋白辅因子如何 影响靶mRNA上miRNA活性的基因调控结果？为了解决这些问题，我们将 利用强大的模式生物秀丽隐杆线虫，并利用多种方法， 定义在体内调节miRNA活性的遗传和分子网络。拟议的工作将建立一个 这将帮助我们了解miRNA功能的错误调节如何导致基因丢失， 在多种疾病中的表达控制。

Project summary Proper control of gene expression is essential for maintenance of cell and tissue homeostasis. Altered regulation of gene expression contributes to a number of diseases including cancer and neurodegenerative and metabolic disorders. One important layer of gene regulation occurs at the post-transcriptional level and is orchestrated by a class of small non-coding RNAs called microRNAs (miRNAs). Alterations in miRNA function contribute to many diseases, yet we lack complete knowledge of how miRNA activity is controlled to differentially repress target genes. The broad goal of the proposed research program is to understand how miRNA activity is regulated in the complex context of a living organism. More specifically, we will address two questions that have limited our understanding of miRNA gene regulatory activity in development and disease. 1. How is miRNA target gene specificity established through regulation of miRNA induced silencing complex (miRISC) programming with a specific miRNA strand? and 2. How do auxiliary miRISC protein cofactors impact the gene-regulatory outcomes of miRNA activity on target mRNAs? To address these questions, we will take advantage of the powerful model organism Caenorhabditis elegans and utilize a number of approaches to define the genetic and molecular networks that regulate miRNA activity in vivo. The proposed work will build a foundation that will help us understand how misregulation of miRNA function contributes to loss of gene expression control in a variety of diseases.