Hypoxia Core

缺氧核心

• 批准号: 10206541
• 负责人: HAL E. BROXMEYER
• 金额: $ 15.44万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10206541
• 关键词: Adult; Air; Applications Grants; Area; Biochemical; Biology; Birth; Blood Cells; Bone Marrow; Cell Death; Cell Differentiation process; Cells; Cellular biology; Clinical; Collection; Communities; Core Grant; Data; Economics; Environment; Evaluation; Event; Exposure to; Gene Expression Profile; General Population; Health Benefit; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Hypoxia; Immune; In Vitro; Indiana; Journals; Life; Maintenance; Mediator of activation protein; Medicine; Mitochondria; Molecular; Mus; Nobel Prize; Non-Malignant; Organ; Oxygen; Phenotype; Physiological; Physiology; Preleukemia; Process; Production; Productivity; Publications; Publishing; Regulation; Reporting; Research; Research Personnel; Resources; Role; Scientist; Services; Shock; Stimulus; Stress; Stromal Cells; TP53 gene; Time; Translations; Umbilical Cord Blood; Universities; Work; clinical efficacy; clinical translation; cost; cyclophilin D; cytokine; hematopoietic cell transplantation; hematopoietic differentiation; improved; in vivo; insight; knockout gene; member; mitochondrial permeability transition pore; mouse model; peripheral blood; progenitor; programs; stem; stress reactivity

This revised shared Hypoxia core (HC) is proposed for the Indiana University (IU) Cooperative Center of Excellence in Hematology (CCEH) to support and enhance research efforts of members of our center, other CCEH centers, and other qualified US investigators in the area of hematopoiesis and nonmalignant hematology. Information generated is critical for better in vivo understanding of phenotypic and functional cellular, molecular, and biochemical aspects of hematopoietic stem (HSC), progenitor (HPC), immune, and stromal cells. This involves regulation of normal hematopoiesis and pre-leukemia in context of their lowered oxygen (O2) environment in vivo. O2 tension within bone marrow (BM;1-5%) and cord blood (CB) or mobilized peripheral blood (mPB; <10%), is lower than in the ambient air (~21% O2) in which they are routinely collected for analysis. While it has been known for >40 years that HSC and HPC grow better ex-vivo in lowered (≤ 5%) O2, our report (Mantel, et. al., Cell, 2015) and more recent work shown in this HC grant project, demonstrated previously unknown information that collection/processing of BM, CB, and mPB in ambient air results in large decreases in phenotypically defined and functional HSC and increased HPC numbers within minutes of cell exposure to ambient air. We termed this process Extra Physiological Shock/Stress (EPHOSS). Collection/processing of cells at 3% O2, such that they are never exposed to ambient air resulted in 2 to 5-fold increases in phenotypically- and functionally-detectable HSC. As well, this manifested as different gene expression patterns and responsiveness to stimuli associated with HSC. Similar changes were also noted with murine pre-leukemic and immune cells. Re-evaluation of hematopoietic function associated with maintenance of HSC and HPC at lowered O2 levels can now be elucidated through the expertise of our HC. New data derived with our hypoxia chamber in the revised HC demonstrates the incredible power of the HC to help the hematopoietic community. Specific Aims of the HC involving normal and non-malignant murine and human hematology are: 1) Provide outstanding, consistent and timely analysis of mouse and human BM, mPB, immune and stromal cells, and human CB, BM, and mPB collected/processed at 3%, as well as other, O2 tensions compared to that in ambient air; 2) Coordinate with the other IU CCEH cores for in-depth analysis of cells collected in hypoxia vs. ambient air; 3) Enhance productivity of our CCEH and other CCEH members, and outside investigators by providing a centralized set of services with reduced cost, and expert guidance not currently available elsewhere; and 4) Provide advice regarding intricacies of such studies, analyses, and overcoming potential problems. The HC provides an economic resource that will add new and significant cutting-edge scientific analysis to greatly advance our current understanding of HSC/HPC and immune and stromal cell biology in ways that will increase their translational use for clinical benefit.

该修订后的共享缺氧核心（HC）是为印第安纳大学（IU）合作中心提出的 血液学卓越（CCEH）支持和增强我们中心成员的研究工作 CCEH中心以及造血和非造血领域的其他合格的美国调查员 血液学。生成的信息对于更好地体内理解表型和功能至关重要 造血茎（HSC），祖细胞（HPC），免疫和免疫和生化方面的细胞，分子和生化方面 基质细胞。这涉及调节正常造血和白血病前的调节，以降低 体内氧气（O2）环境。骨髓内的O2张力（BM； 1-5％）和脐带血（CB）或动员 外围血（MPB； <10％），低于周围空气（〜21％O2），以常规收集它们 用于分析。虽然已经知道HSC和HPC在降低的降低（≤5％）中已经知道了40年 O2，我们的报告（Mantel等，Cell，2015年）以及此HC赠款项目中显示的最新工作 以前未知的信息表明，环境空气中BM，CB和MPB的收集/处理导致大量 在细胞几分钟之内的表观定义和功能性HSC的减少和功能性HSC和HPC数量增加 暴露于环境空气。我们称这一过程额外的生理休克/压力（Ephoss）。 3％O2的细胞收集/加工，因此它们永远不会暴露于环境空气中，导致2至5倍 在表型和功能检测的HSC上增加。同样，这表现为不同的基因 表达模式和对与HSC相关的刺激的反应性。还指出了类似的变化 鼠前白血病和免疫细胞。与维护相关的造血功能的重新评估 现在，可以通过我们的HC的专业知识来阐明HSC和HPC的HSC和HPC。新数据 在修订后的HC中使用我们的缺氧室得出的表明，HC具有令人难以置信的力量 造血社区。 HC的特定目的涉及正常和非恶性鼠和人类 血液学是：1）对小鼠和人类BM，MPB，提供出色，一致且及时的分析 免疫和基质细胞，以及以3％的收集/处理的人CB，BM和MPB以及其他O2 与环境空气中的紧张关系相比； 2）与其他IU CCEH核心协调，以深入分析 在缺氧与环境空气中收集的细胞； 3）提高我们的CCEH和其他CCEH成员的生产率，以及 外部调查人员通过提供成本降低的集中式服务，而专家指导而不是 目前在其他地方可用； 4）提供有关此类研究，分析和 克服潜在问题。 HC提供了一种经济资源，将增加新的大量 尖端的科学分析，以极大地提高我们当前对HSC/HPC和免疫的理解 基质细胞生物学的方式将增加其转化用途以临床益处。