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: 9111901
• 负责人: Owen James Tamplin
• 金额: $ 16.33万
• 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/9111901
• 关键词: Address; Adrenergic Receptor; Adult; Animal Model; Antibodies; Award; Back; Behavior; Binding; Biological Assay; Biological Models; Biomedical Research; Blood; Blood Cells; Blood Circulation; Bone Marrow; Boston; CXCL12 gene; CXCR4 Receptors; Cell Count; Cell Culture Techniques; Cell Transplants; Cell model; Cells; Chemicals; Circadian Rhythms; Clinical; Colony-Forming Units Assay; Communication; Data; Disease; Distant; Dopamine Receptor; Dose; Embryo; Engraftment; Enhancers; Environment; Fetal Liver; Genetic; Genetic Screening; Genetic screening method; Goals; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Hematopoietic stem cells; Home environment; Homeostasis; Human; Image; Individual; Institution; Interleukin-1; JAK2 gene; Label; Lead; Learning; Life; Ligands; Maintenance; Mammals; Marrow; Mentors; Microscopy; Mus; Mutation; Myeloproliferative disease; Nature; Nerve; Nervous System Physiology; Nervous System Trauma; Nervous system structure; Neurobiology; Neuromodulator; Neurons; Neuroregulator; Norepinephrine; Paper; Patient-Focused Outcomes; Patients; Pediatric Hospitals; Preparation; Production; Publishing; Regulation; Reporter; Research; Research Personnel; Resolution; Series; Serotonin Agonists; Signal Pathway; Signal Transduction; Site; Source; Staging; Stem cells; Stromal Cells; Supporting Cell; Sympathetic Nervous System; System; Testing; Training; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Transgenic Organisms; Translating; Translations; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Work; Zebrafish; blood vessel development; career; cell motility; cell type; chemical genetics; curative treatments; cytokine; developmental genetics; drug candidate; graduate student; hematopoietic tissue; improved; inhibitor/antagonist; insight; interest; medical schools; nerve supply; novel; post-doctoral training; programs; public health relevance; response; screening; small molecule; small molecule libraries; stem; stem cell division; stem cell niche; stem cell population; tool; undergraduate student

 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，血管和神经一起形成，并连接造血的远端部位。随着我们了解的越来越多，我们发现血细胞与神经元共享许多信号通路。我们开始了解到血液和神经系统之间存在着联系。我们现在知道，交感神经系统（SNS）支配一个称为造血干细胞（HSC）的特殊微环境。来自交感神经元的一种信号是去甲肾上腺素，其被基质支持细胞和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CXCL 12，其是小生境中HSC最重要的保留信号之一，表达同源受体CXCR 4。然后，HSC被释放到循环中或从骨髓中“动员”出来。这种动员和植入回到生态位的循环每天由SNS调节，并遵循昼夜节律。骨髓小生境神经支配的功能意义最近变得明显，因为交感神经损伤可导致某些血液疾病的进展。许多骨髓增生性肿瘤患者的HSC存在JAK 2（V617 F）突变，该突变可驱动白细胞介素-1 β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（Arranz等人，Nature 2014）。本研究旨在了解神经系统对HSC生态位的调控机制，寻找新的HSC及其生态位的神经调节因子。斑马鱼和小鼠将被用作互补的模式生物。新的HSC特异性转基因和高分辨率显微镜已经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翻译。本研究的目的是重新创造一个离体调控环境，使临床移植前的HSC的扩增和维持。 我的长期职业目标是在一家大型研究机构领导我自己的生物医学研究小组。我在发育遗传学和斑马鱼造血博士后培训方面的强大背景为这项拟议的研究做了很好的准备。我非常幸运地在波士顿儿童医院和哈佛医学院找到了理想的培训环境。我的导师伦纳德博士。Zon非常支持我的研究，并帮助我准备过渡到独立调查员。我在实验室里指导了哈佛的研究生和本科生，还有三名技术人员，从中受益匪浅。我的共同导师乔治博士Q。Daley，Charles Lin，and Christopher A.沃尔什提供了他们的专业知识，在哺乳动物HSC测定，活成像的HSC生态位，神经生物学的主题，分别。这个奖项将让我继续接受他们的指导和支持，然后开始我自己的独立研究计划，将探索造血和神经系统之间的接口。