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.

项目总结/摘要 所有类型的血细胞都来源于单一的造血干细胞（HSC）前体。HSC必须 通过自我更新的对称细胞分裂平衡扩增， 不对称细胞分裂（ACD）以产生功能性血液系统。当ACD被破坏时， 通常以特定血细胞类型的不成比例产生或不受控制的 造血祖细胞的扩增。该项目的目标是了解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， 在造血祖细胞中使用基于RNAi的耗竭鉴定分子参与者， 免疫荧光技术。目的2将确定ACD如何影响在稳态时的谱系选择 通过在体内平衡期间和在应激物（例如 缺氧或损伤最终，这些实验将有助于阐明一个空间和机制， 同时建立一个果蝇模型，这将有助于加速进展 在哺乳动物ACD造血中起作用。 我的职业目标是成为一个成功的独立研究员在顶级学术机构。我 我的目标是领导一个研究项目，调查如何从利基和微环境的外在线索 影响细胞极性和细胞分裂以影响HSC自我更新和血细胞谱系选择。实现 为了实现这些目标，我将利用基本细胞生物学和细胞骨架研究方面的技术和培训， 造血的遗传解剖和先进的成像技术。我会继续进行我提议的训练 在Utpal Banerjee博士的指导下，Utpal Banerjee博士在使用遗传技术解剖 用果蝇作为模型系统来研究造血的分子基础。此外，我的咨询 委员会将提供关键的支持和资源，帮助我将我的发现转化为哺乳动物系统， 开发尖端成像技术，在体内平衡期间实时监测血液系统， 应力我将在国家和国际会议上介绍我的工作并传播我的发现， 推进我的研究，建立合作，并在造血领域建立自己。该项目将 通过帮助我建立使用的可行性，促进我过渡到一个独立的研究职位 研究果蝇造血过程中的ACD和初步工作的基础。UCLA是一个 追求这项工作的绝佳场所，因为它提供了丰富的资源，研究合作， 专业发展机会，帮助我推进我的职业生涯。作为一名初级教员，我将参加 培训活动侧重于领导技能、赠款撰写、在高影响力期刊上发表文章、实验室 管理和指导，以帮助我发展所需的技能，运行一个成功的研究团队。