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，重点是在临床相关的应力下单细胞水平的造血干细胞分化。我的长期研究目的是确定造血干细胞如何在维持平衡的血液系统中协调，以及该协调的调节机制与血液疾病的调节机制如何相关。我在普林斯顿大学（Ihor R. Lemischka）博士的指导下，在普林斯顿大学（Ihor R. Lemischka）的指导下，在分子生物学方面具有强大的背景，并在斯坦福大学欧文·韦斯曼（Irving L. Weissman）博士的指导下进行了细胞生物学专业知识。我精通几种编程语言，包括C/C ++，R，Matlab和Python，并且可以独立设计并进行现代定量生物学所需的先进统计分析。使用这些跨学科技能，我最近开发了一种新型的单细胞体内跟踪系统特征，高灵敏度和高吞吐量。我们使用该系统的初步研究证实了小鼠HSC谱系偏差的先前报道。此外，我们发现了一种先前未发现的现象：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克隆子集的急剧扩张。更引人注目的是，虽然通常在辐照介导的移植后观察到谱系偏置和克隆膨胀，但它们在无条件的移植后不存在。因此，我们假设谱系偏差和克隆扩张不是先天的HSC特征，而是由外源造血应激（例如辐照）引发的行为。在这笔赠款中，我们建议在各种移植条件下（K99期）进一步检验小鼠中的这一假设，并确定谱系偏见和克隆扩张是否相关（K99期 / R00相）以及它们是否是HSC克隆（R00相）的先天确定性特征。除了这些体内小鼠研究外，我们还将调查在克隆水平（R00期）中置入小鼠中的人类HSC。这些提出的研究将阐明造血稳态如何在破坏后重新建立，并将辐照诱导的作用与自然先天细胞特性分开。结果将有助于促进与不平衡血液系统相关的疾病的治疗，并可能导致溶液减少临床应用和职业中辐射的副作用，并在持续的低辐射暴露水平。我的K99阶段培训将由杰出的造血干细胞专家欧文·韦斯曼（Irving L.除了允许我完成拟议的研究外，K99培训还将大大增强我的研究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应用程序做准备。