MicroRNAs as Determinants of Endothelial Progenitor Cell Senescence

MicroRNA 作为内皮祖细胞衰老的决定因素

• 批准号: 8440279
• 负责人: CHUNMING DONG
• 金额: $ 31.47万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440279
• 关键词: Affect; Age; Aging; Aging-Related Process; Animals; Apolipoprotein E; Atherosclerosis; Biological; Blood Vessels; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; CDKN2A gene; Candidate Disease Gene; Cell Aging; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Characteristics; Chronic; Competence; Complement; Coupled; Data; Development; Effectiveness; Engraftment; Functional disorder; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genomics; Goals; In Vitro; Inflammation; Knowledge; Mediating; Messenger RNA; MicroRNAs; Modification; Molecular; Molecular Profiling; Mus; Pathway interactions; Pattern; Phenotype; Play; Prevention; Process; Publishing; Regulation; Reporting; Risk; Risk Factors; Role; Series; Signal Transduction; Stem cells; Testing; Time; Tissues; Treatment Efficacy; Vascular Endothelial Growth Factors; Wild Type Mouse; Work; age effect; aged; atherogenesis; base; cardiovascular risk factor; cell type; design; functional disability; genome-wide; improved; in vivo; innovation; knowledge base; mRNA Expression; novel strategies; overexpression; p19ARF; paracrine; public health relevance; regenerative; repaired; research study; self-renewal; senescence; stem

DESCRIPTION (provided by applicant): MicroRNAs (miRNA) play important roles in regulating the plasticity and functions of stem and progenitor cells. MiRNA expression pattern undergoes dynamic changes during aging in a tissue and gene specific manner, implicating a putative role of specific miRNA and their target genes in mediating senescent changes and functional impairment of endothelial progenitor cells (EPC)/lineage negative bone marrow cells (linBMC). We and others have shown that EPC are actively involved in vascular repair. Senescent EPC, such as those from aged animals, have impaired repair capacity, which is coupled with atherosclerosis development. Therefore, EPC senescence may partially mediate the strong predisposing effects of aging and other cardiovascular risk factors on atherosclerosis. To determine the molecular underpinnings for age associated EPC senescence in the presence and absence of percholesterolemia, we have performed miRNA and mRNA profiling in EPC/linBMC from young and aged apoE/ and wild type mice. We have identified miR10A*/ miR21, miR29c and miR126, as well as their target genes, to be differentially expressed in young and aged linBMC. These miRNA control distinct aspects of linBMC competency. Specifically, the miR10a*/ miR21hmga2p16Ink4a/p19Arf axis mainly regulates linBMC self renewal potential, whereas miR29cklf2amiR126 spred1 VEGF signaling predominantly governs linBMC differentiation capacity. We have generated evidence supporting the role of miRNA in regulating linBMC activities in vivo. With this proposal, we have developed a comprehensive set of experiments to characterize the combined effects of these two candidate pathways in regulating linBMC senescence in vitro. We will also study additional miRNA/mRNA candidates derived from analysis of our genome wide profiling data and published reports. Then, we will determine the functional significance of miR10a*/miR21hmga2-p16Ink4a/p19Arf axis and miR29c-klf2a-miR126spred1 VEGF signaling as well as additional candidate miRNA and their target genes (validated in vitro) in affecting the effectiveness of linBMC in vascular repair and atherosclerosis development in apoE/mice in vivo. This integrated and innovative approach will allow us to thoroughly characterize the molecular mechanisms underlying linBMC senescence and functional impairment, which will facilitate the design of novel strategies to slow down/reverse the senescent process of EPC/linBMC (therefore to reduce atherosclerosis risk) and to enhance the therapeutic efficacy of bone marrow based cellular treatments for atherosclerosis using genetic modifications.

描述（由申请人提供）：MicroRNA（miRNA）在调节干细胞和祖细胞的可塑性和功能中发挥着重要作用。 miRNA 表达模式在衰老过程中以组织和基因特异性方式经历动态变化，暗示特定 miRNA 及其靶基因在介导内皮祖细胞 (EPC)/谱系阴性骨髓细胞 (linBMC) 衰老变化和功能损伤中的假定作用。我们和其他人已经证明 EPC 积极参与血管修复。衰老的 EPC，例如来自老年动物的 EPC，其修复能力受损，并伴有动脉粥样硬化的发展。因此，EPC衰老可能部分介导衰老和其他心血管危险因素对动脉粥样硬化的强烈诱发作用。为了确定在存在和不存在高胆固醇血症的情况下与年龄相关的 EPC 衰老的分子基础，我们对年轻和老年 apoE/ 和野生型小鼠的 EPC/linBMC 进行了 miRNA 和 mRNA 分析。我们已经鉴定出 miR10A*/ miR21、miR29c 和 miR126 及其靶基因在年轻和老年 linBMC 中存在差异表达。这些 miRNA 控制 linBMC 能力的不同方面。具体来说，miR10a*/ miR21hmga2 p16Ink4a/p19Arf 轴主要调节 linBMC 自我更新潜力，而 miR29cklf2a miR126 spred1 VEGF 信号主要控制 linBMC 分化能力。我们已经获得证据支持 miRNA 在调节体内 linBMC 活性中的作用。根据这一建议，我们开发了一套全面的实验来表征这两种候选途径在体外调节 linBMC 衰老方面的综合作用。我们还将研究通过分析我们的全基因组分析数据和已发表的报告得出的其他 miRNA/mRNA 候选者。然后，我们将确定 miR10a*/miR21hmga2- p16Ink4a/p19Arf 轴和 miR29c- klf2a- miR126spred1 VEGF 信号传导以及其他候选 miRNA 及其靶基因（体外验证）在影响 linBMC 有效性方面的功能意义在 apoE/小鼠体内血管修复和动脉粥样硬化发展中的作用。这种综合和创新的方法将使我们能够彻底表征 linBMC 衰老和功能损伤的分子机制，这将有助于设计新策略来减缓/逆转 EPC/linBMC 的衰老过程（从而降低动脉粥样硬化风险）并使用基因修饰增强基于骨髓的细胞治疗对动脉粥样硬化的治疗效果。