MicroRNAs' Role in Hematopoietic Lineage Differentiation

MicroRNA 在造血谱系分化中的作用

• 批准号: 7459579
• 负责人: CHANG-ZHENG CHEN
• 金额: $ 37.87万
• 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/7459579
• 关键词: Address; Affect; Animals; Apoptosis; B cell differentiation; B-Lymphocytes; Base Sequence; Biological Assay; Biological Process; Bone Marrow; Breathing; Caenorhabditis elegans; Candidate Disease Gene; Cell physiology; Cells; Class; Cultured Cells; Development; Drosophila genus; Ectopic Expression; Engineering; Functional RNA; Gene Expression; Gene Expression Regulation; Gene Targeting; Generations; Genes; Growth; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; In Vitro; Laboratories; Lead; Light; Link; Maintenance; Mediating; Methods; MicroRNAs; Molecular; Monitor; Mus; Nematoda; Neurons; Organ; Pattern; Plants; Play; Population; Principal Investigator; RNA Interference; Regulation; Regulator Genes; Reporter; Reporter Genes; Research; Research Proposals; Role; Science; Signal Pathway; Site; Small Interfering RNA; Stem cells; Time; Untranslated RNA; design; expression cloning; gene interaction; gene repression; in vivo; insight; knock-down; leukemia; lipid metabolism; novel therapeutics; plant growth/development; prevent; research study; sensor; stem

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）：最近对微小RNA（miRNA）、RNA干扰、短干扰RNA和小调节RNA的发现揭示了在动物和植物发育中由短RNA介导的潜在广泛的基因调控机制。 miRNA 是一类丰富的约 22 nt 内源非编码 RNA。有些已被证明通过在转录后水平控制基因表达在植物和动物发育中发挥重要作用。最近证明miR-181可以在体外和体内促进B细胞分化，这为miRNA在脊椎动物发育中具有调节作用提供了第一个证据(Chen等人，Science，2004，303：83)。然而，miRNA 在脊椎动物发育中发挥作用的例子仍然很少，并且 miRNA 发挥其功能的分子机制也很大程度上不清楚。本研究提案解决了这些基本问题，旨在确定造血过程中 miRNA 介导的转录后基因调控回路的潜在广泛影响。通过 miRNA 克隆和表达分析，我们鉴定了一组可能在谱系分化中发挥重要作用的造血 miRNA。我们将尝试定义这些 miRNA 在造血谱系分化的各个方面的功能，以便我们能够确定 miRNA 在造血过程中更广泛的作用（目标 1）。通过明确的体外和体内分化测定，我们将能够剖析 miRNA 调节的潜在信号通路，确定 miRNA 基因的结构和功能关系，定义 miRNA 作用的祖细胞群，并描述 miRNA 控制的细胞过程（目标 2）。最后，我们将结合计算和实验方法来识别造血 miRNA 的功能相关靶基因（目标 3）。了解 miRNA 在造血过程中的生物学功能将有助于阐明 miRNA 在血液疾病中的作用，并可能产生新的治疗策略来纠正包括白血病在内的许多血液疾病。拟议的研究还将为那些寻求将 miRNA 纳入其他生物过程的人们提供方法、见解和灵感。