Small RNAs in Stem Cell Differentiation and Neural Development

小RNA在干细胞分化和神经发育中的作用

• 批准号: 7437264
• 负责人: Robert Blelloch
• 金额: $ 33.79万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7437264
• 关键词: Address; Adult; Anabolism; Biogenesis; Bioinformatics; Biological Sciences; Cell Cycle; Cell Death; Cell Differentiation process; Cell Nucleus; Cell Proliferation; Cell Survival; Cell model; Cell physiology; Cells; Centromere; Characteristics; Chromatin; Chromosomal Instability; Class; Classification; Cleaved cell; Collaborations; Complex; Condition; Constitution; Cytoplasm; Defect; Depth; Development; Diagnosis; Dicer Enzyme; Double-Stranded RNA; Embryo; Embryonic Development; Functional RNA; G1 Phase; Gene Silencing; Gene Targeting; Genes; Genome; Goals; Grant; Human Development; In Vitro; Individual; Knock-out; Knockout Mice; Knowledge; Laboratories; Left; Maintenance; Maps; Mental disorders; Messenger RNA; MicroRNAs; Microprocessor; Mitotic; Modeling; Molecular; Mus; Null Lymphocytes; Organ; Pathway interactions; Phenotype; Play; Population; Process; Proteins; RNA; RNA Processing; RNA-Binding Proteins; Regulation; Reporter; Research Personnel; Role; Side; Small Interfering RNA; Small RNA; Staging; Stem cells; System; Technology; Transcriptional Regulation; Translational Regulation; Vision; Work; base; embryonic stem cell; gene function; human DICER1 protein; human disease; in vivo; insight; mRNA Stability; mammalian genome; model development; mouse model; nerve stem cell; neurodevelopment; novel; pluripotency; postnatal; pre-miRNA; pri-miRNA; programs; relating to nervous system; research study; self-renewal; stem; stem cell therapy; tool; tumor

DESCRIPTION (provided by applicant): Understanding the regulatory networks that direct stem cell differentiation is critical to realizing the promise of stem cell therapy. Differentiation requires large and rapid shifts in the mRNA and protein constitution of cells. Small RNAs are particularly well suited to perform this task. For example, microRNAs, a subclass of small RNAs, are predicted to individually regulate hundreds of target genes simultaneously. The overall goal of this proposal is to systematically study the role of small RNAs in embryonic and neural stem cell differentiation. This is a collaborative grant including experts in stem cells and small RNAs. To address the overall objective of the grant, a mouse embryonic stem cell model was developed that specifically knocks-out microRNA function thereby separating the roles of the two main classes of small RNAs, microRNAs and siRNAs, in mammalian development. This model is based on the conditional deletion of the RNA binding protein DGCR8, which is required for the processing of pri- to pre-microRNAs. The specific aims of this grant include: 1) the analysis of role of microRNAs in stem cell proliferation based on preliminary results showing that DGCR8 null ES cells accumulate in the G1 phase of the cell cycle, 2) characterization of the role of miRNAs in stem cell differentiation based on initial findings that DGCR8 null ES cells continue to self-renew even under strict differentiation conditions. 3) identification of novel non-microRNA small RNAs that are required for stem cell function. This aim is based on the finding that the DGCR8 null ES cell phenotype differs from that of the Dicer null phenotype. Completion of this project will help identify regulatory networks that can be manipulated to differentiate and potentially de-differentiate cells along specific developmental pathways. Small RNAs are a relatively new class of cell regulators whose pervasiveness and global effects on gene function suggests they have a central role in both normal and abnormal human development. In support of this, recent evidence shows they have an important role in the development of tumors. Therefore, a systematic analysis of their function in embryonic and somatic stem cells as proposed in this grant should provide important insights into how they influence and can be used to diagnose and treat human disease.

描述（由申请人提供）：了解指导干细胞分化的调控网络对于实现干细胞治疗的承诺至关重要。分化需要细胞的mRNA和蛋白质结构发生巨大而快速的变化。小rna特别适合执行这项任务。例如，小rna的一个亚类microrna被预测可以同时单独调节数百个靶基因。本提案的总体目标是系统地研究小rna在胚胎和神经干细胞分化中的作用。这是一项包括干细胞和小rna专家的合作资助。为了实现该基金的总体目标，研究人员开发了一种小鼠胚胎干细胞模型，该模型特异性地敲除了microRNA的功能，从而分离了两类主要小rna （microRNA和sirna）在哺乳动物发育中的作用。该模型基于RNA结合蛋白DGCR8的条件缺失，这是加工pri- to pre-microRNAs所必需的。该资助的具体目的包括：1)基于初步结果分析microrna在干细胞增殖中的作用，初步结果显示DGCR8无效的ES细胞在细胞周期的G1期积累，2)基于初步发现DGCR8无效的ES细胞即使在严格的分化条件下也能继续自我更新，表征microrna在干细胞分化中的作用。3)鉴定干细胞功能所需的新型非microrna小rna。这一目标是基于DGCR8零ES细胞表型不同于Dicer零表型的发现。这个项目的完成将有助于确定调控网络，可以操纵分化和潜在的去分化细胞沿着特定的发育途径。小rna是一类相对较新的细胞调节因子，其对基因功能的普遍性和全球性影响表明它们在正常和异常的人类发育中都起着核心作用。为了支持这一点，最近的证据表明它们在肿瘤的发展中起着重要作用。因此，对它们在胚胎和体细胞干细胞中的功能进行系统分析，将为了解它们如何影响和用于诊断和治疗人类疾病提供重要见解。