Hypoxia Core

缺氧核心

• 批准号: 10473863
• 负责人: HAL E. BROXMEYER
• 金额: $ 13.67万
• 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/10473863
• 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.

这个修订的共享缺氧核心(HC)是为印第安纳大学(IU)合作中心 血液学卓越奖(CCEH)，以支持和加强我们中心成员的研究工作，其他 CCEH中心，以及其他在造血和非恶性领域的合格美国调查人员 血液学。产生的信息对于在体内更好地理解表型和功能是至关重要的 造血干细胞(HSC)、祖细胞(HPC)、免疫和免疫的细胞、分子和生化方面 基质细胞。这涉及到在其降低的背景下对正常造血和白血病前期的调节 体内氧气(O2)环境。骨髓(BM；1-5%)和脐带血(CB)内或动员的氧分压 外周血液(mpb；&lt；10%)低于环境空气中(~21%O2)。 以供分析。虽然40年前就已经知道，在低浓度条件下，造血干细胞和高密度脂蛋白在体外生长得更好(≤5%)。 O2，我们的报告(Mantel，et.以及在这个HC赠款项目中展示的更新的工作，展示了 收集/处理环境空气中的BM、CB和MPB导致大量 表型定义的和功能性的HSC减少，HPC数量在细胞数分钟内增加 暴露在环境空气中。我们将这一过程称为额外生理性休克/应激(EPHOSS)。 在3%氧气中收集/处理细胞，使它们永远不会暴露在环境空气中，结果是2到5倍 表型和功能上可检测到的HSC的增加。同样，这也表现为不同的基因 与HSC相关的表达模式和对刺激的反应性。类似的变化也被注意到了 小鼠白血病前期细胞和免疫细胞。与维护相关的造血功能的再评估 现在可以通过我们的HC的专业知识来阐明HSC和HPC在较低的O2水平下的情况。新数据 与我们的缺氧室在修订的HC证明了令人难以置信的力量，以帮助 造血界。涉及正常和非恶性小鼠和人的HC的特定目标 血液学是：1)提供出色、一致和及时的人和鼠骨髓、MPB、 免疫和基质细胞，以及人CB、BM和MPB在3%以及其他O2条件下采集/处理 与环境空气中的张力进行比较；2)与其他IU CCEH核心协调，以深入分析 在低氧和环境空气中收集的细胞；3)提高我们CCEH和其他CCEH成员的生产力，以及 通过提供一套成本更低的集中服务和专家指导 目前在其他地方可用；以及4)提供关于此类研究、分析和 克服潜在问题。HC提供了一种经济资源，将增加新的和重要的 尖端科学分析，极大地促进了我们目前对HSC/HPC和免疫和 基质细胞生物学，将增加它们的翻译使用，为临床带来好处。