MicroRNAs' Role in Hematopoietic Lineage Differentiation

MicroRNA 在造血谱系分化中的作用

• 批准号: 7090857
• 负责人: CHANG-ZHENG CHEN
• 金额: $ 38.93万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7090857
• 关键词: biological signal transduction; biotechnology; cell differentiation; cell growth regulation; cytogenetics; gene expression; gene interaction; genetic regulation; hematopoiesis; laboratory mouse; microRNAs; microarray technology; protein structure function

DESCRIPTION (provided by applicant): The recent discoveries of microRNAs (miRNAs), RNA interference, short interfering RNAs, and small modulatory RNAs have revealed potentially widespread gene regulatory mechanisms that are mediated by short RNAs in animal and plant development. miRNAs are an abundant class of~22 nt endogenous noncoding RNAs. Some have been shown to play an important role in plant and animal development by controlling gene expression at the posttranscriptional level. Recently it was demonstrated that miR-181 could promote B-cell differentiation in vitro and in vivo, providing the first evidence that miRNAs have regulatory roles in vertebrate development (Chen et al., Science, 2004, 303:83). However, examples of miRNAs functioning in vertebrate development are still rare, and the molecular mechanisms through which miRNAs exert their functions are largely unclear. This research proposal addresses these fundamental questions and aims to establish the potential widespread influences of miRNA-mediated posttranscriptional gene regulatory circuitries during hematopoiesis. Through miRNA cloning and expression analyses, we have identified a set of hematopoietic miRNAs that may play important roles in lineage differentiation. We will try to define the functions of these miRNAs in various aspects of hematopoietic lineage differentiation so that we can establish broader roles for miRNAs in hematopoiesis (aim 1). With defined in vitro and in vivo differentiation assays we will be able to dissect the potential signaling pathways that are regulated by miRNAs, determine the structural and functional relationships of miRNA genes, define the progenitor cell population(s) that miRNAs act on, and delineate the cellular processes controlled by miRNAs (aim 2). Finally, we will combine computational and experimental approaches to identify the functionally relevant target genes of hematopoietic miRNAs (aim 3). Understanding the biological functions of miRNAs in hematopoiesis will shed light on the roles of miRNAs in hematological disorders and could lead to novel therapeutic strategies to correct many hematological disorders, including leukemias. The proposed research will also provide methods, insights, and inspiration to those seeking to place miRNAs into other biological processes.

描述（由申请人提供）：MicroRNA（miRNA），RNA干扰，短干扰RNA和小型调节RNA的最新发现可能揭示了由简短的RNA在动物和植物发育中介导的广泛的基因调节机制。 miRNA是〜22 nt内源性非编码RNA的丰富类。已经证明，通过在转录后水平控制基因表达，有些人在动植物发育中起着重要作用。最近证明，miR-181可以在体外和体内促进B细胞分化，这提供了第一个证据，表明miRNA在脊椎动物发育中具有调节作用（Chen等，Science，2004，303：83）。然而，在脊椎动物发育中起作用的miRNA的实例仍然很少见，并且miRNA施加其功能的分子机制在很大程度上不清楚。这项研究提案解决了这些基本问题，并旨在建立造血期间miRNA介导的后基因调节循环的潜在广泛影响。通过miRNA克隆和表达分析，我们已经确定了一组造血miRNA，这些miRNA可能在谱系分化中起重要作用。我们将尝试在造血谱系的各个方面定义这些miRNA的功能，以便我们可以在造血中建立更广泛的miRNA作用（AIM 1）。通过定义的体外和体内分化测定，我们将能够剖析受miRNA调节的潜在信号传导途径，确定miRNA基因的结构和功能关系，定义miRNA的作用于祖细胞群，并描绘由miRNAS控制的细胞过程（AIM 2）。最后，我们将结合计算和实验方法，以识别造血miRNA的功能相关靶基因（AIM 3）。了解miRNA在造血中的生物学功能将阐明miRNA在血液学疾病中的作用，并可能导致新的治疗策略，以纠正包括白血病在内的许多血液学疾病。拟议的研究还将为那些寻求将miRNA置于其他生物学过程的人们提供方法，见解和灵感。