Lineage bias and clonal expansion of hematopoietic stem cell differentiation

造血干细胞分化的谱系偏向和克隆扩增

• 批准号: 8280736
• 负责人: Rong Lu
• 金额: $ 13.32万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-08 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8280736
• 关键词: Address; Adverse effects; Antibodies; Area; Attention; Background Radiation; Behavior; Biological Assay; Biology; Blood; Blood Cells; Cell Lineage; Cells; Cellular biology; Characteristics; Clinical; Clonal Expansion; Clonality; Data; Defect; Disease; Doctor of Philosophy; Dysmyelopoietic Syndromes; Environment; Equilibrium; Exhibits; Future; Goals; Grant; Health; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Heterogeneity; Homeostasis; Hospitals; Human; Impairment; Individual; Institutes; Investigation; Knowledge; Lead; Lymphoid; Mediating; Mentors; Molecular Biology; Mus; Myelodysplastic/Myeloproliferative Disease; Myelogenous; Myeloproliferative disease; Nuclear; Occupations; Phase; Phenotype; Physiological; Positioning Attribute; Programming Languages; Property; Pythons; Radiation; Regenerative Medicine; Regimen; Regulation; Reporting; Research; Research Personnel; SLAM protein; Signal Transduction; Solutions; Stem cells; Stress; System; Techniques; Testing; Time; Training; Transplantation; Transplantation Conditioning; Universities; Vascular blood supply; Wit; bone; career; cell motility; cell type; chemotherapy; clinical application; clinically relevant; conditioning; design; dosage; experience; improved; in vivo; irradiation; medical schools; novel; preconditioning; radiologist; research study; skills; stem cell biology; stem cell differentiation

DESCRIPTION (provided by applicant): My immediate career goal is to become an independent investigator of stem cells, focusing on hematopoietic stem cell differentiation at the single cell level under clinically relevant stresses. My long-term research goal is to determine how hematopoietic stem cells are coordinated in sustaining a balanced blood system and how the regulatory mechanisms of this coordination are related to blood disorders. I have a strong background in molecular biology from my PhD training at Princeton University under the guidance of Dr. Ihor R. Lemischka and expertise in cell biology under the mentoring of Dr. Irving L. Weissman at Stanford University. I am proficient with several programming languages including C/C++, R, Matlab, and Python, and I can independently design and carry out the advanced statistical analyses required for modern quantitative biology. Using these cross-disciplinary skills, I have recently developed a novel, single cell in vivo tracking system featurig high sensitivity and high throughput. Our preliminary studies using this system confirm previous reports of HSC lineage bias in mice. In addition, we have discovered a previously undetected phenomenon: the majority of blood cells after irradiation-mediated transplantation are derived from the dramatic expansion of a small subset of engrafted HSC clones. More strikingly, while lineage bias and clonal expansion are commonly observed after irradiation-mediated transplantation, they are not present after unconditioned transplantation. Therefore, we hypothesize that lineage bias and clonal expansion are not innate HSC characteristics, but instead are behaviors initiated by exogenous hematopoietic stresses such as irradiation. In this grant, we propose to further test this hypothesis in mice under various transplantation conditions (K99 phase) as well as to determine whether lineage bias and clonal expansion are related (K99 phase / R00 phase) and whether they are innate deterministic features of HSC clones (R00 phase). In addition to these in vivo mice studies, we will also investigate human HSCs xenotransplanted into mice at the clonal level (R00 phase). These proposed studies will elucidate how hematopoietic homeostasis is re-established after disruption and will separate irradiation-induced effects from natural innate cellular properties. The results will help to improe the treatment of diseases associated with an unbalanced blood system and may lead to solutions that reduce the side effects of radiation in clinical applications and in occupations wit constant low levels of radiation exposure. My K99 phase training will be mentored by the distinguished hematopoietic stem cell expert Dr. Irving L. Weissman, in a world-class institutional environment at the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University School of Medicine. In addition to allowing me to finish the proposed research, the K99 training will also substantially enhance my knowledge and experience with the clinical applications of my research. In addition, it will help me locate an independent research position and provide the initial support to prepare for my first R01 application.

描述（由申请人提供）：我的近期职业目标是成为干细胞的独立研究者，专注于临床相关压力下单细胞水平的造血干细胞分化。我的长期研究目标是确定造血干细胞如何协调以维持血液系统的平衡，以及这种协调的调节机制如何与血液疾病相关。我在普林斯顿大学 Ihor R. Lemischka 博士的指导下攻读博士学位，在分子生物学方面拥有深厚的背景，并在斯坦福大学 Irving L. Weissman 博士的指导下获得细胞生物学方面的专业知识。精通C/C++、R、Matlab、Python等多种编程语言，能够独立设计和进行现代定量生物学所需的高级统计分析。利用这些跨学科技能，我最近开发了一种新型单细胞体内跟踪系统，具有高灵敏度和高通量。我们使用该系统的初步研究证实了之前关于小鼠 HSC 谱系偏向的报道。此外，我们还发现了一个以前未被发现的现象：辐射介导移植后的大多数血细胞源自一小部分移植的HSC克隆的急剧扩增。更引人注目的是，虽然在辐射介导的移植后通常观察到谱系偏倚和克隆扩增，但在无条件移植后则不存在。因此，我们假设谱系偏向和克隆扩张不是 HSC 的先天特征，而是由外源性造血应激（例如辐射）引发的行为。在这笔资助中，我们建议在不同移植条件下（K99期）的小鼠中进一步测试这一假设，并确定谱系偏倚和克隆扩增是否相关（K99期/R00期）以及它们是否是HSC的先天确定性特征克隆（R00 期）。除了这些小鼠体内研究之外，我们还将研究在克隆水平（R00 期）将人类 HSC 异种移植到小鼠体内。这些拟议的研究将阐明造血稳态在破坏后如何​​重新建立，并将辐射诱导的效应与天然的先天细胞特性分开。研究结果将有助于改善与血液系统不平衡相关的疾病的治疗，并可能找到减少临床应用和辐射暴露水平持续较低的职业中辐射副作用的解决方案。我的K99阶段训练将由杰出的造血干细胞专家Irving L. Weissman博士在斯坦福大学医学院干细胞生物学和再生医学研究所世界一流的机构环境中进行指导。除了让我完成拟议的研究之外，K99 培训还将大大增强我对研究的临床应用的知识和经验。此外，它将帮助我找到一个独立的研究职位，并为我的第一个 R01 申请做准备提供初步支持。