Mechanisms of Asymmetric Cell Division in Developmental Hematopoiesis

发育造血过程中细胞不对称分裂的机制

• 批准号: 10583514
• 负责人: Lauren Monica Goins
• 金额: --
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2023-02-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10583514
• 关键词: Acceleration; Advisory Committees; Affect; Aging; Anemia; Biological Models; Blood; Blood Cells; Bone Marrow; Cell Count; Cell Cycle; Cell Lineage; Cell Polarity; Cell division; Cells; Cellular biology; Characteristics; Collaborations; Committee Members; Complex; Cues; Cytoskeleton; Development; Disease; Dissection; Drosophila genus; Equilibrium; Faculty; Fluorescent Antibody Technique; Foundations; Genetic; Genetic Techniques; Goals; Grant; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Human; Hypoxia; Image; Imaging Techniques; Imaging technology; Immune System Diseases; In Vitro; Injury; Institution; International; Journals; Knowledge; Laboratories; Leadership; Link; Maintenance; Mammals; Mentors; Mentorship; Modeling; Molecular; Monitor; Myeloproliferative disease; Oxygen; Pathway interactions; Population; Positioning Attribute; Production; Proteins; Publishing; RNA Interference; Regulation; Research; Research Design; Research Personnel; Resolution; Resources; Role; Running; Scientist; Signal Transduction; Stress; System; Techniques; Time; Training; Training Activity; Translating; Work; Writing; career; career development; cell type; deprivation; experience; experimental study; genetic regulatory protein; hematopoietic stem cell aging; hematopoietic stem cell quiescence; hematopoietic stem cell self-renewal; in vivo; member; mutant; nutrient deprivation; progenitor; programs; real time monitoring; response; rho GTP-Binding Proteins; self-renewal; skills; stressor; symposium; tool; transcriptomics

Project Summary/Abstract All blood cell types are derived from a single hematopoietic stem cell (HSC) precursor. HSCs must balance expansion through self-renewing symmetric cell division with differentiation of progeny cells through asymmetric cell division (ACD) to produce a functional blood system. When ACD is disrupted, profound blood disorders occur often characterized by disproportionate production of specific blood cell types or uncontrolled expansion of blood progenitors. The goal of the proposed project is to understand how ACD influences developmental hematopoiesis and blood cell fate choice. Aim 1 will characterize how ACD occurs by identifying molecular players using RNAi-based depletion in hematopoietic progenitors and immunofluorescence techniques. Aim 2 will determine how ACD influences lineage choice during homeostasis and stress by monitoring blood cell fate upon disruption of ACD during homeostasis and after stressors such as oxygen deprivation or injury. Ultimately, these experiments will help elucidate a spatial and mechanistic model for ACD in hematopoiesis while establishing a Drosophila model that will help accelerate advancements in mammalian ACD hematopoiesis work. My career goal is to become a successful independent researcher at a top-tier academic institution. I aim to lead a research program that investigates how extrinsic cues from the niche and microenvironment influence cell polarity and cell division to impact HSC self-renewal and blood cell lineage choice. To achieve these goals, I will utilize techniques and training in basic cell biology and cytoskeleton research combined with genetic dissection of hematopoiesis and advanced imaging techniques. I will pursue the proposed training under the mentorship of Dr. Utpal Banerjee who has extensive experience using genetic techniques to dissect the molecular underpinnings of hematopoiesis using Drosophila as a model system. Additionally, my advisory committee will provide key support and resources to help me translate my findings to mammalian systems and develop cutting edge imaging techniques to monitor the blood system in real-time during homeostasis and stress. I will present my work and disseminate my findings at national and international conferences to help advance my research, build collaborations, and establish myself in the hematopoiesis field. This project will facilitate my transition to an independent research position by helping me establish the feasibility of using Drosophila to study ACD during hematopoiesis and a foundation of preliminary work to build upon. UCLA is an excellent place to pursue this work as it provides a rich landscape of resources, research collaborations, and professional development opportunities to help me advance my career. As a junior faculty, I will take part in training activities focused on leadership skills, grant writing, publishing in high impact journals, laboratory management, and mentoring to help me develop the skills needed to run a successful research team.

项目概要/摘要 所有血细胞类型均源自单一造血干细胞 (HSC) 前体。 HSC 必须 通过自我更新的对称细胞分裂和子代细胞的分化来平衡扩张 不对称细胞分裂（ACD）产生功能性血液系统。当ACD被破坏时，深刻的血液 发生的疾病通常以特定血细胞类型的不成比例的产生或不受控制为特征 血液祖细胞的扩增。拟议项目的目标是了解 ACD 如何影响 发育性造血和血细胞命运选择。目标 1 将描述 ACD 如何发生： 使用基于 RNAi 的造血祖细胞耗竭来识别分子参与者 免疫荧光技术。目标 2 将确定 ACD 如何影响稳态期间的谱系选择 通过监测体内平衡期间 ACD 破坏时以及压力源后的血细胞命运来监测血细胞的命运 如缺氧或受伤。最终，这些实验将有助于阐明空间和机制 造血 ACD 模型，同时建立果蝇模型，这将有助于加速进展 在哺乳动物ACD造血工作中。 我的职业目标是成为顶级学术机构的一名成功的独立研究员。我 旨在领导一项研究计划，调查利基和微环境的外在线索如何 影响细胞极性和细胞分裂，进而影响 HSC 自我更新和血细胞谱系选择。达到 为了实现这些目标，我将利用基础细胞生物学和细胞骨架研究的技术和培训，并结合 造血的基因解剖和先进的成像技术。我将继续接受建议的培训 在 Utpal Banerjee 博士的指导下，Utpal Banerjee 博士在使用基因技术进行解剖方面拥有丰富的经验 使用果蝇作为模型系统研究造血的分子基础。另外，我的建议 委员会将提供关键支持和资源，帮助我将我的发现转化为哺乳动物系统和 开发尖端成像技术来实时监测血液系统的稳态和 压力。我将在国内和国际会议上展示我的工作并传播我的发现，以帮助 推进我的研究，建立合作，并在造血领域确立自己的地位。该项目将 通过帮助我确定使用的可行性，促进我过渡到独立研究职位 果蝇研究造血过程中的 ACD 和前期工作的基础。加州大学洛杉矶分校是一所 从事这项工作的绝佳场所，因为它提供了丰富的资源、研究合作和 专业发展机会帮助我推进我的职业生涯。作为一名初级教师，我将参加 培训活动侧重于领导技能、资助写作、在高影响力期刊上发表文章、实验室 管理和指导，帮助我培养管理一支成功的研究团队所需的技能。