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.

项目概要： 我近期的职业目标是成为干细胞的独立研究者，重点关注 在临床相关应激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平衡的血液 系统以及这种协调的调节机制如何与血液疾病相关。我有很强的 我在普林斯顿大学在 Ihor 博士的指导下获得了博士学位，获得了分子生物学背景 R. Lemischka 和斯坦福大学 Irving L. Weissman 博士指导下的细胞生物学专业知识 大学。我精通多种编程语言，包括 C/C++、R、Matlab 和 Python，并且我 能够独立设计和进行现代定量所需的高级统计分析 生物学。利用这些跨学科技能，我最近开发了一种新颖的单细胞体内跟踪技术 系统具有高灵敏度和高通量的特点。我们使用该系统的初步研究证实 先前关于小鼠 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部分血细胞来源于 一小部分移植的 HSC 克隆的急剧扩增。更引人注目的是，虽然谱系偏差和克隆 扩增通常在放射介导的移植后观察到，但在放射介导的移植后不存在 无条件移植。因此，我们假设谱系偏倚和克隆扩张不是天生的 HSC 特征，而是由外源性造血应激引发的行为，例如 辐照。在这笔资助中，我们建议在接受各种移植的小鼠中进一步测试这一假设 条件（K99 阶段）以及确定谱系偏差和克隆扩增是否相关（K99 阶段/R00 阶段）以及它们是否是 HSC 克隆的先天确定性特征（R00 阶段）。此外 对于这些体内小鼠研究，我们还将研究人类 HSC 异种移植到小鼠体内的克隆 电平（R00 阶段）。这些拟议的研究将阐明造血稳态是如何重建的 破坏后，会将辐射引起的效应与自然固有的细胞特性分开。结果 将有助于改善与血液系统不平衡相关的疾病的治疗，并可能导致 减少临床应用和持续低辐射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干指导 细胞专家 Irving L. Weissman 博士在干细胞研究所世界一流的机构环境中 斯坦福大学医学院生物学和再生医学。除了允许我 完成拟议的研究，K99培训也将大大提高我的知识和经验 以及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 并为我的第一个 R01 申请做准备提供初步支持。