Hypoxia Core

缺氧核心

• 批准号: 10681262
• 负责人: HAL E. BROXMEYER
• 金额: $ 14.29万
• 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/10681262
• 关键词: Adult; Air; Applications Grants; Area; Biochemical; Biology; Birth; Blood Cells; Bone Marrow; Cell Death; Cell Differentiation Induction; Cells; Cellular biology; Clinical; Collecting Cell; 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; Knockout Mice; Learning; Life; Maintenance; Mediator; Medicine; Mitochondria; Molecular; Mus; Nobel Prize; Non-Malignant; Organ; Oxygen; Phenotype; Physiological; Physiology; Preleukemia; Process; Production; Productivity; Publications; Publishing; Qualifying; Regulation; Reporting; Research; Research Personnel; Resources; Role; Scientist; Services; Shock; Stimulus; Stress; Stromal Cells; TP53 gene; Umbilical Cord Blood; Universities; Work; clinical efficacy; clinical translation; cost; cyclophilin D; cytokine; hematopoietic cell transplantation; improved; in vivo; insight; knockout gene; member; mitochondrial permeability transition pore; mouse model; peripheral blood; progenitor; programs; stem; translational potential

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.

该修订后的共享低氧核心（HC）被提议用于印第安纳州大学（IU）合作中心， 卓越的血液学（CCEH），以支持和加强我们中心成员的研究工作，其他 CCEH中心和造血和非恶性肿瘤领域的其他合格美国研究者 血液学所产生的信息对于更好地在体内理解表型和功能性细胞因子是至关重要的。 造血干细胞（HSC）、祖细胞（HPC）、免疫和 基质细胞这涉及正常造血和白血病前期在其降低的背景下的调节。 氧（O2）环境。骨髓（BM;1-5%）和脐带血（CB）内的O2张力或动员 外周血（mPB; <10%）低于常规采集的环境空气（~ 21%O2） 用于分析虽然已经知道>40年，但HSC和HPC在较低（≤ 5%）浓度下离体生长更好， O2，我们的报告（曼特尔，等。例如，细胞，2015年）和最近的工作显示，在这个HC赠款项目，证明 先前未知的信息表明，环境空气中BM、CB和mPB的收集/处理导致大量 在细胞凋亡后数分钟内，表型确定的和功能性HSC减少，HPC数量增加 暴露于环境空气中。我们称这个过程为额外的生理冲击/应激（EPHOSS）。 在3%O2下收集/处理细胞，使其从不暴露于环境空气，导致2至5倍的 增加表型和功能可检测的HSC。同样，这表现为不同的基因 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， 小鼠白血病前期细胞和免疫细胞。与维持相关的造血功能再评价 通过我们HC的专业知识，现在可以阐明在低O2水平下HSC和HPC的变化。新数据 在修订后的HC中使用我们的低氧室得出的结果表明，HC具有令人难以置信的力量， 造血共同体涉及正常和非恶性小鼠和人的HC的特定目的 血液学：1）提供小鼠和人BM、mPB 在3% O2下采集/处理的免疫和基质细胞以及人CB、BM和mPB，以及其他 2）与其他IU CCEH核心协调，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成员的生产力， 外部调查员，提供一套集中的服务，降低成本，专家指导， 4）就此类研究、分析和评估的复杂性提供建议， 克服潜在的问题。人道主义协调员提供了一种经济资源， 尖端的科学分析，大大推进我们目前对HSC/HPC和免疫的理解， 基质细胞生物学的方式，将增加其翻译使用的临床效益。