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: 8787299
• 负责人: Rong Lu
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-10 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8787299
• 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; 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

Project Summary: 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 featuring 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 improve 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 with 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.

项目摘要： 我的直接职业目标是成为干细胞的独立研究者，重点是 在临床相关应力下，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在维持平衡的血液中协调 系统以及该协调的调节机制与血液疾病有关。我很强 我在普林斯顿大学的博士培训的分子生物学背景下在Ihor博士的指导下 R. Lemischka和细胞生物学专业知识在斯坦福大学的Irving L. Weissman博士的指导下 大学。我精通几种编程语言，包括C/C ++，R，Matlab和Python和我 可以独立设计并进行现代定量所需的先进统计分析 生物学。使用这些跨学科技能，我最近开发了一个新颖的单细胞体内跟踪 具有高灵敏度和高吞吐量的系统。我们使用此系统的初步研究证实 先前关于小鼠HSC谱系偏差的报道。此外，我们发现了先前未发现的 现象：辐照介导的移植后的大多数血细胞源自 一小部分植入的HSC克隆的急剧扩张。更引人注目的是，谱系偏见和克隆 通常在辐照介导的移植后观察到膨胀，在 无条件的移植。因此，我们假设谱系偏见和克隆扩张不是先天的 HSC的特征，而是由外源造血应力引发的行为，例如 辐照。在这笔赠款中，我们建议在各种移植下进一步检验小鼠中的假设 条件（K99期）以及确定谱系偏差和克隆扩张是否相关（K99 相 / R00相）以及它们是否是HSC克隆（R00相）的天生确定性特征。此外 对于这些体内小鼠的研究，我们还将研究在克隆的小鼠中的人类HSC植入小鼠 电平（R00阶段）。这些提出的研究将阐明如何重新建立造血稳态 破坏后，将使辐照诱导的作用与天然先天细胞特性分开。结果 将有助于改善与不平衡血液系统相关的疾病的治疗，并可能导致 减少临床应用和恒定低职业中辐射副作用的解决方案 辐射暴露水平。我的K99阶段训练将由杰出的造血茎进行指导 细胞专家欧文·韦斯曼（Irving L. Weissman）博士在干细胞研究所的世界一流机构环境中 斯坦福大学医学院的生物学和再生医学。除了允许我 完成拟议的研究，K99培训还将大大增强我的知识和经验 随着我的研究的临床应用。此外，它将帮助我找到一个独立的研究职位 并提供初始支持以准备我的第一个R01应用程序。