Regulation of Hemangiogenesis by Hypoxia-Inducible Factor 1 and microRNAs

缺氧诱导因子 1 和 microRNA 对血管生成的调节

• 批准号: 7674199
• 负责人: Gregg L Semenza
• 金额: $ 4.1万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 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/7674199
• 关键词: Adult; Applications Grants; Blood; Blood Cells; Blood Vessels; Cardiovascular Diseases; Cell Lineage; Cell Maintenance; Cells; DNA Sequence; Development; Disease; Endosteum; Gene Expression; Hematopoiesis; Hematopoietic; Hypoxia; Lead; Life; Marrow; Mediating; Messenger RNA; MicroRNAs; Molecular; Physiological; Play; Population; Proteins; Regulation; Role; Stem cells; Techniques; Therapeutic; Transplantation; Undifferentiated; Vascularization; base; cell type; clinical application; hypoxia inducible factor 1; in vivo; neuronal cell body; peripheral blood; progenitor; programs; response; self-renewal; stem; transcription factor

DESCRIPTION (provided by applicant): The existence of hematopoietic stem-progenitor cells, which are present in the adult marrow and capable of self-renewal and differentiation into the progenitors that give rise to all types of mature blood cells, has been known for over half a century. More recently, endothelial stem-progenitor cells have also been identified. There remain several major obstacles to a more complete understanding of the molecular mechanisms underlying the self-renewal and differentiation of these stem-progenitor cells. First, these cells are present in low abundance and are difficult to purify from their more differentiated progeny. Techniques are needed to expand these cells, while maintaining their capacity for subsequent differentiation, in order that they might be better studied and utilized therapeutically. Second, in the case of endothelial stem-progenitors, thus far it has not been possible to establish a hierarchical lineage similar to what has been described for hematopoietic cells. Third, it is not clear whether the hematopoietic and endothelial stem-progenitors in adult marrow are themselves the descendants of a common stem cell, the hemangioblast. The molecular basis for development is the elaboration of discrete programs of gene expression in each cell type. Two central mechanisms for regulating gene expression are transcription factors, which determine the rate at which DNA sequences are transcribed into mRNA, and microRNAs, which determine the rate at which mRNAs are transcribed into protein. We hypothesize that there are key transcription factors and microRNAs which play critical roles in regulating the self-renewal and differentiation of hematopoietic and endothelial stem-progenitor cells. These cells are essential for hemangiogenesis, the formation of blood and blood vessels, respectively, which in turn are essential for the continuous delivery of O2 to all cells of the body. Within the marrow, undifferentiated cells are located along the endosteum, whereas more differentiated cells are located in proximity to the highly vascularized marrow cavity, from whence they enter the peripheral blood. The endosteal niche is hypoxic and may promote stem cell maintenance, whereas increased O2 levels in the vascular niche may promote proliferation and differentiation. We hypothesize that O2 functions as a developmental regulator for hemangiogenic cells, such that stem vs progenitor cell populations may require different O2 concentrations. The transcriptional regulator hypoxia-inducible factor 1 (HIF-1) mediates adaptive developmental and physiological responses to hypoxia and plays an essential, but only partially defined role, in hemangiogenesis. In this grant application, we propose to delineate the molecular mechanisms whereby HIF-1 and microRNAs regulate hemangiogenesis. By doing so, we hope to: better identify and characterize hemangiogenic progenitor cell lineages; direct the differentiation of stem and progenitor cells to desired cell fates; and develop new strategies for therapeutic utilization of these cells for in vivo hematopoiesis and vascularization.

描述(申请人提供)：半个多世纪以来，人们已经知道存在造血干细胞-祖细胞，这种干细胞存在于成人骨髓中，能够自我更新和分化为祖细胞，产生各种类型的成熟血细胞。最近，也发现了内皮干细胞-祖细胞。要更全面地了解这些干细胞-祖细胞自我更新和分化的分子机制，仍然存在几个主要障碍。首先，这些细胞的丰度很低，很难从分化程度较高的后代中纯化出来。需要技术来扩增这些细胞，同时保持它们随后分化的能力，以便更好地研究它们并将其用于治疗。其次，在内皮干细胞的情况下，到目前为止，还不可能建立一个类似于造血细胞所描述的等级谱系。第三，目前尚不清楚成人骨髓中的造血祖细胞和内皮干细胞本身是否是一种常见干细胞--血管母细胞的后代。发育的分子基础是在每种细胞类型中详细阐述基因表达的离散程序。调节基因表达的两个核心机制是转录因子和microRNAs，前者决定了DNA序列转录成mRNA的速度，后者决定了mRNAs转录成蛋白质的速度。我们假设存在关键的转录因子和microRNAs，它们在调节造血干细胞和内皮干细胞的自我更新和分化方面发挥关键作用。这些细胞对血管生成、血管的形成和血管的形成是必不可少的，而血管又是氧气持续输送到身体所有细胞所必需的。在骨髓中，未分化的细胞位于骨内膜，而更多的分化细胞位于高度血管化的骨髓腔附近，它们从那里进入外周血液。骨内壁龛是低氧的，可能会促进干细胞的维持，而血管壁龛中氧气水平的增加可能会促进增殖和分化。我们假设O2作为血管生成细胞的发育调节器发挥作用，因此干细胞和祖细胞群体可能需要不同的O2浓度。转录调节因子低氧诱导因子1(HIF-1)介导对低氧的适应性发育和生理反应，在血管生成中起重要但仅部分确定的作用。在这项拨款申请中，我们建议描述HIF-1和microRNAs调节血管生成的分子机制。通过这样做，我们希望：更好地鉴定和表征血管生成祖细胞谱系；引导干细胞和祖细胞分化为所需的细胞命运；并开发新的治疗策略，利用这些细胞在体内进行造血和血管形成。