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: 10875215
• 负责人: Lauren Monica Goins
• 金额: $ 15.21万
• 依托单位: STANFORD UNIVERSITY
• 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 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10875215
• 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/文摘