核受体RXRα和microRNA的相互作用及其作用机制和功能的研究

细胞核受体和miRNA具有重要的生理和病理功能。它们之间的间接作用已有报道，但是它们之间的直接相互作用以及其中的功能至今还不清楚。我们的前期研究揭示核受体RXRα能够直接结合pre-miR-103a-2和pre-miR-145，而且这种结合可能参与调控miRNA103的转录后成熟。我们还发现RXRα的配体可能通过调节此相互作用进而改善小鼠糖尿病模型的胰岛素耐受。据此本课题将在分子、细胞和动物水平，用多学科交叉的方法深入研究RXRα和miRNA直接相互作用的类型和方式、相互作用的调节机制、相互作用的生理学功能、相互作用的紊乱与疾病的关联以及基于此相互作用的疾病干预手段。本课题的开展将展示核受体和miRNA直接相互作用的概念以及其互作的方式和机制；同时本课题将揭示基于此相互作用的RXRα和miRNA功能的新的调节方式，以及与此相互作用相关的代谢性疾病和肿瘤的新的发病机制和治疗方案。

Both nuclear receptors and microRNAs (miRNAs) play pivotal roles in a plethora of biological and pathological processes. Their indirect interactions and regulations have been reported, however, their direct interactions and the underlying mechanisms and the physiopathological activities are not known. Our preliminary studies revealed that Retinoid x receptor alpha (RXRα), a nuclear receptor, directly bound to pre-miR-103a-2 and pre-miR-145, and promoted the maturation of pre-miR-103a-2 to produce miR-103a. Z-10, a nitro-ligand of RXRα, dramatically improved glucose tolerance in diabetes mice model, which might be due to its strong inhibition of the expression of miR-103a, a miRNA highly associated with insulin resistance. In this proposed research, we will apply integrated multidisciplinary approaches to explore the modes, mechanisms, regulations and functions of the direct interactions between RXRα and miRNAs. We will focus on studying the following questions, 1) Which miRNAs directly interact with RXRα? 2) What are the interacting modes of RXRα and miRNAs? 3) How to regulate the interactions of RXRα and miRNAs? 4) What are the functional interplays between RXRα and miRNAs through their direct interactions? 5) How does the dysregulation of the interaction cause metabolic diseases and cancers? 6) How to devise approaches to target the interactions for disease therapies. Results from our project will show that RXRα and miRNAs interact directly to exert their functions, which is a novel concept in the fields of nuclear receptor and miRNA. Our project will also reveal the novel physiological regulations and functions of the interaction of RXRα and miRNAs, as well as the interaction-based new pathological mechanisms and therapeutic approaches for metabolic diseases and cancers.