Regulation of Hematopoietic Stem Cell Self-renewal and Differentiation

造血干细胞自我更新和分化的调控

• 批准号: 7672856
• 负责人: RAVI BHATIA
• 金额: $ 4.15万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7672856
• 关键词: Address; Arts; Bioinformatics; Biology; Biomedical Engineering; Blood; Blood Vessels; Cardiac; Cell Differentiation process; Cells; Development; Disease; Functional RNA; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Goals; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; In Vitro; Individual; Investigation; Lung; Malignant Neoplasms; Mediating; Messenger RNA; Methods; MicroRNAs; Microfluidics; Modeling; Nanotechnology; Pluripotent Stem Cells; Population; RNA; Regulation; Regulator Genes; Relative (related person); Role; Screening procedure; Specificity; Staging; Stem Cell Development; Stem cells; Technology; Therapeutic; Tissues; Translations; Transplantation; base; cell fate specification; clinical application; gene therapy; human tissue; improved; in vivo; multidisciplinary; progenitor; self-renewal; stem; transcription factor

DESCRIPTION (provided by applicant): Improved understanding of gene regulatory networks in stem and progenitor cells is essential for the development of strategies for manipulating progenitor cell fates for experimental and therapeutic purposes. MicroRNAs (miRNAs) are small non-coding regulatory RNAs that reduce translation and/or stability of complementary target messenger RNAs (mRNAs). miRNA represents a critical mechanism for the control of gene expression and cell fate specification in addition to transcription factors (TF) that are traditionally associated with this role. The hematopoietic system provides an outstanding model for investigation of the role of miRNAs in regulation of stem/progenitor cell fate since cell populations at different stages of differentiation are well characterized. Previous studies support a critical role for miRNA in regulating hematopoiesis but have only focused on a few candidate miRNAs. The relative abundance and specificity of expression for most miRNAs remains to be investigated, and the role of expressed miRNA singly or cooperatively in regulating gene expression and determining cell fate and function remains poorly understood. The goal of the proposed studies is to investigate the role of miRNAs in regulation of hematopoietic stem and progenitor cell differentiation and self-renewal. A multidisciplinary team of collaborators with expertise in hematopoiesis, RNA biology, bioengineering/nanotechnology and bioinformatics will develop and apply state- of-the-art technologies to address this important goal. Project 1 will study miRNA expression and gene regulation in hematopoietic stem and progenitor cells. miRNA expression and transcriptome composition in precisely defined progenitor populations will be studied using ultra-high throughput sequencing approaches and regulatory networks of miRNAs, transcription factors and their target genes at different stages of differentiation will be investigated. Project 2 will study the function of expressed miRNAs in lineage specification and self-renewal of hematopoietic stem and progenitor cells. High-throughput methods for screening miRNA function will be developed and putative function validated by detailed in vitro and in vivo analyses. Project 3 will study miRNA mediated gene regulation in hematopoietic stem and progenitor cells at the single cell level. A newly developed microfluidic bioprocessor will be used to investigate miRNA-mediated gene regulation in individual progenitor cells. The proposed studies have clear translational applications to manipulation of stem and progenitor cell populations for therapeutics, including transplantation, directed differentiation and gene therapy. These studies will also provide a basis for understanding perturbations in miRNA-mediated gene regulation in pathological states including malignancies. The sequencing, screening and bioengineering approaches developed for these studies have considerable potential for broader application within the consortium for investigation of the role of miRNA in cell fate determination in progenitor populations in cardiac, vascular and pulmonary tissues, and for investigating human tissue specific stem cell development from pluripotent stem cells.

描述（由申请人提供）：提高对干细胞和祖细胞基因调控网络的理解对于开发用于实验和治疗目的的操纵祖细胞命运的策略至关重要。MicroRNAs （miRNAs）是一种小的非编码调控rna，可降低互补靶信使rna （mrna）的翻译和/或稳定性。miRNA是控制基因表达和细胞命运规范的关键机制，而转录因子（TF）传统上与此作用相关。造血系统为研究mirna在干细胞/祖细胞命运调控中的作用提供了一个出色的模型，因为不同分化阶段的细胞群体都有很好的特征。先前的研究支持miRNA在调节造血中的关键作用，但只关注少数候选miRNA。大多数miRNA的相对丰度和表达特异性仍有待研究，表达的miRNA单独或协同调节基因表达和决定细胞命运和功能的作用仍然知之甚少。这些研究的目的是研究mirna在造血干细胞和祖细胞分化和自我更新调控中的作用。一个由造血、RNA生物学、生物工程/纳米技术和生物信息学专家组成的多学科合作团队将开发和应用最先进的技术来实现这一重要目标。