Controlling Influences of Oxygen Tension and CD26/DPP4 Enzymatic Activity on Regulation of Hematopoietic Stem/Progenitor Cells and Hematopoiesis During Health, Ageing, and Disease

控制氧张力和 CD26/DPP4 酶活性对健康、衰老和疾病期间造血干/祖细胞和造血作用的调节的影响

• 批准号: 10219824
• 负责人: HAL E. BROXMEYER
• 金额: $ 76.81万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219824
• 关键词: Address; Aging; Air; Animal Model; Basic Science; Blood Cells; Bone Marrow; CCL3 gene; CSF3 gene; CXCL12 gene; Cell Culture Techniques; Cell Cycle; Cell model; Cell surface; Cells; Clinical Investigator; Collaborations; Collection; Controlled Environment; Dipeptidyl-Peptidase IV; Disease; Engraftment; Funding; Gene Expression; Goals; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Health Benefit; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Heterogeneity; Human; Hypoxia; IL3 Gene; Laboratories; Malignant - descriptor; Metabolism; Methodology; Mus; National Heart, Lung, and Blood Institute; Non-Malignant; Oxygen; Patients; Phenotype; Physiological; Play; Procedures; Process; Reactive Oxygen Species; Recovery; Regenerative Medicine; Regulation; Role; Running; Shock; Source; Stress; System; Therapeutic; Time; Translating; Treatment Efficacy; Umbilical Cord Blood; United States National Institutes of Health; cell type; chemokine; cytokine; hematopoietic cell transplantation; in vivo; innovation; insight; personalized medicine; pre-clinical; protein expression; receptor binding; response; stem; stem cell function; stem cells

While much is known about hematopoietic stem (HSC) and progenitor cell (HPC) phenotype (cell surface and intracellular markers), heterogeneity, and function, there is still more to be learned, especially for how best to use and manipulate these cells for therapeutic advantage. The PI has run a continuously NIH-funded basic science laboratory for over 39 years. His goal continues to be to translate mechanistic insight for pre-clinical cell and animal models, and in collaboration with clinical investigators for clinical utility. The purpose of this NIH R35 application is to allow the PI and his lab ample uninterrupted time to pursue new ideas and creative approaches in context of two active NHLBI R01 grants. HL 056416 focuses on oxygen tension, metabolism, function and optimal collection and activities of HSCs from bone marrow (BM) and cord blood (CB), findings with implications for other stem and progenitor cell types. Exposure of mouse BM or human CB cells to ambient air within minutes induces Extra Physiological Shock Stress (EPHOSS), causing loss of HSCs through Reactive Oxygen Species (ROS) induced differentiation, not cell death. EPHOSS may have implications for personalized medicine to more accurately evaluate gene expression profiles and cell responsiveness in situations more closely related to O2 tension of cells in their in vivo microenvironment, compared to cells collected/processed in an artificial environment of ambient air. HL 112669 assesses effects of CD26/Dipeptidylpeptidase (DPP)4 in truncating selected cytokines (e.g. GM-CSF, G-CSF, IL-3, EPO, TPO) and chemokines (e.g. CXCL12, CCL3), thus changing their receptor-binding, cellular and intracellular activities. This has relevance to all systems in which cytokines/chemokines play a regulatory role. Blocking EPHOSS or inhibiting CD26/DPP4 enzymatic activity results in collection of increased numbers of HSCs. We will produce new information on mechanistic regulation of hematopoiesis. Our hypotheses and significance are: understanding EPHOSS and enzymatic activities of DPP4 and their manipulation will lead to a better understanding of HSC/HPC functions in health, ageing, and disease, information that can be used to accelerate patient recovery from stress/disease and for human CB hematopoietic cell transplantation (HCT). Our goals are to determine: 1) what hypoxic collection, processing, cell culture, and in vivo engraftment, and DPP4 inhibition, informs us about the regulation of HSCs, HPCs, and hematopoiesis during health, in response to stress, ageing and disease; 2) other means to compensate for effects of EPHOSS for more efficient HCT, and 3) differences in cell cycle status and gene and protein expression profile of HSCs and HPCs collected/processed in hypoxia/air and/or -/+ DPP4 inhibition. The innovation lies in paradigm changing concepts to be addressed with state-of-the-art methodologies. What we find can be translated to other cell sources for HCT, and for cells/procedures in the emerging field of regenerative medicine to enhance treatment efficacy.

虽然对造血干细胞（HSC）和祖细胞（HPC）表型（细胞表面和细胞外基质）有很多了解，但是， 细胞内标记物），异质性和功能，还有更多的东西要学，特别是如何最好地 利用和操纵这些细胞以获得治疗优势。PI已经运行了一个持续的NIH资助的基本 科学实验室超过39年。他的目标仍然是将机械学见解转化为临床前 细胞和动物模型，并与临床研究人员合作进行临床应用。这个NIH的目的是 R35应用程序是为了让PI和他的实验室有充足的不间断的时间来追求新的想法和创造性 在两个积极的NHLBI R 01赠款的背景下的方法。HL 056416专注于氧张力，新陈代谢， 从骨髓（BM）和脐带血（CB）中收集HSC的功能和最佳收集和活性，发现 对其他干细胞和祖细胞类型也有影响。将小鼠BM或人CB细胞暴露于 环境空气在几分钟内诱导额外的生理休克应激（EPHOSS），导致HSC损失， 活性氧（ROS）诱导分化，而不是细胞死亡。EPHOSS可能会影响到 个性化药物，以更准确地评估基因表达谱和细胞反应性， 与细胞相比，与细胞在其体内微环境中的O2张力更密切相关的情况 在周围空气的人工环境中收集/处理。HL 112669评估了 CD 26/二肽基肽酶（DPP）4截短选定的细胞因子（例如GM-CSF、G-CSF、IL-3、EPO、TPO） 和趋化因子（例如CXCL 12、CCL 3），从而改变它们的受体结合、细胞和细胞内活性。 这与细胞因子/趋化因子发挥调节作用的所有系统相关。阻塞EPHOSS或 抑制CD 26/DPP 4酶活性导致收集的HSC数量增加。我们将生产 关于造血机制调节的新信息。我们的假设和意义是： 了解EPHOSS和DPP 4的酶活性及其操纵将导致更好的 了解HSC/HPC在健康、衰老和疾病中的功能，这些信息可用于 加速患者从压力/疾病中恢复以及用于人CB造血细胞移植（HCT）。 我们的目标是确定：1）缺氧收集、处理、细胞培养和体内移植，以及 DPP 4抑制，告诉我们关于健康期间HSC，HPC和造血的调节， 压力、衰老和疾病; 2）补偿EPHOSS效应的其他方法，以获得更有效的HCT， HSC和HPC的细胞周期状态和基因及蛋白表达谱的差异 在缺氧/空气和/或-/+ DPP 4抑制中收集/处理。创新在于范式变革 这些概念将以最先进的方法加以解决。我们的发现可以转化到其他细胞 HCT的来源，以及再生医学新兴领域的细胞/程序，以加强治疗 功效

项目成果

Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease.

• DOI: 10.1056/nejmoa2027372
• 发表时间: 2021-01-07
• 期刊: The New England journal of medicine
• 作者: Farag SS;Abu Zaid M;Schwartz JE;Thakrar TC;Blakley AJ;Abonour R;Robertson MJ;Broxmeyer HE;Zhang S
• 通讯作者: Zhang S