Live imaging to determine the behavior of endogenous hematopoietic stem cells

实时成像以确定内源性造血干细胞的行为

• 批准号: 9260178
• 负责人: Owen James Tamplin
• 金额: $ 7.02万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-16 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260178
• 关键词: Live; imaging; determine; behavior; endogenous

 DESCRIPTION (provided by applicant): From the earliest stages of development, blood vessels and nerves form together and connect distant sites of hematopoiesis. As we learn more, we are finding that blood cells share many signaling pathways with neurons. We are beginning to understand that there is communication between the blood and nervous systems. We now know that the sympathetic nervous system (SNS) innervates a specialized microenvironment called the niche that is home to hematopoietic stem cells (HSCs). One signal from sympathetic neurons is norepinephrine that is bound by ß-adrenergic receptors on stromal support cells and HSCs themselves. This signal instructs stromal cells to down-regulate the ligand CXCL12, one of the most important retention signals for HSCs in the niche, which express the cognate receptor CXCR4. HSCs are then released into circulation or "mobilized" out of the bone marrow. This cycle of mobilization and engraftment back into the niche is regulated daily by the SNS and follows circadian rhythms. The functional significance of bone marrow niche innervation has recently become apparent, as sympathetic nerve damage can contribute to the progression of some blood diseases. Many patients with myeloproliferative neoplasms have HSC with a JAK2(V617F) mutation that drives interleukin-1 ß production. HSCs that overproduce this cytokine actually cause SNS injury within the niche that ultimately accelerates the disease (Arranz et al. Nature 2014). The goal of this research plan is to understand the mechanisms of HSC niche regulation by the nervous system and to find new neuroregulators of HSCs and the niche. The zebrafish and mouse will be used as complementary model organisms. Novel HSC-specific transgenics and high resolution microscopy has established the zebrafish as an important HSC niche model (Tamplin et al. Cell 2014). The high degree of conservation between zebrafish and mammals means findings can be easily translated. The goal of this research is to recreate a regulatory environment ex vivo that will allow expansion and maintenance of HSC prior to clinical transplantation. My long-term career goal is to lead my own biomedical research group at a major research institution. My strong background in developmental genetics and postdoctoral training in zebrafish hematopoiesis has been excellent preparation for this proposed research. I have been very fortunate to find an ideal training environment at Boston Children's Hospital and Harvard Medical School. My mentor Dr. Leonard I. Zon is highly supportive of my research and is helping me prepare for the transition to independent investigator. I have benefited from mentoring Harvard graduate and undergraduate students in the lab, and three technicians. My co-mentors Drs. George Q. Daley, Charles Lin, and Christopher A. Walsh have offered their expertise in the topics of mammalian HSC assays, live imaging of the HSC niche, and neurobiology, respectively. This award will allow me to continue receiving their guidance and support before starting my own independent research program that will explore the interface between the hematopoietic and nervous systems.

 描述（由申请人提供）：从发育的最早阶段开始，血管和神经就一起形成并连接远处的造血部位。随着我们了解的更多，我们发现血细胞与神经元共享许多信号通路。我们开始了解血液和神经系统之间存在着沟通。我们现在知道，交感神经系统 (SNS) 支配着一个称为“生态位”的特殊微环境，该环境是造血干细胞 (HSC) 的所在地。来自交感神经元的一种信号是去甲肾上腺素，它与基质支持细胞和 HSC 本身上的 β-肾上腺素能受体结合。该信号指示基质细胞下调配体 CXCL12，这是微环境中 HSC 最重要的保留信号之一，表达同源受体 CXCR4。然后，HSC 被释放到循环系统中或从骨髓中“动员”出来。这种动员和植入回生态位的循环每天由 SNS 调节，并遵循昼夜节律。骨髓生态位神经支配的功能意义最近变得明显，因为交感神经损伤可能导致某些血液疾病的进展。许多骨髓增生性肿瘤患者的 HSC 带有 JAK2(V617F) 突变，可驱动白细胞介素 1ß 的产生。过度产生这种细胞因子的 HSC 实际上会导致生态位内的 SNS 损伤，最终加速疾病的发展 (Arranz et al. Nature 2014)。该研究计划的目标是了解神经系统对HSC微环境的调节机制，并寻找新的HSC和微环境的神经调节因子。斑马鱼和小鼠将被用作互补的模式生物。新型 HSC 特异性转基因技术和高分辨率显微镜已将斑马鱼确立为重要的 HSC 生态位模型 (Tamplin et al. Cell 2014)。斑马鱼和哺乳动物之间的高度保护意味着研究结果可以很容易地转化。这项研究的目标是在体外重建一个监管环境，以便在临床移植前能够扩增和维持 HSC。 我的长期职业目标是在一家主要研究机构领导自己的生物医学研究小组。我在发育遗传学和斑马鱼造血方面的博士后培训方面的深厚背景为这项拟议的研究做好了充分的准备。我非常幸运能够在波士顿儿童医院和哈佛医学院找到理想的培训环境。我的导师 Leonard I. Zon 博士非常支持我的研究，并帮助我为向独立研究者的过渡做好准备。我从在实验室指导哈佛大学研究生和本科生以及三名技术人员中受益匪浅。我的共同导师博士。 George Q. Daley、Charles Lin 和 Christopher A. Walsh 分别提供了哺乳动物 HSC 检测、HSC 生态位实时成像和神经生物学等主题的专业知识。这个奖项将使我能够在开始我自己的独立研究计划之前继续接受他们的指导和支持，该计划将探索造血系统和神经系统之间的接口。