Kinetic Characterization of Hematopoietic Stem Cell Differentiation During Homeostasis And Pathological Conditions

稳态和病理条件下造血干细胞分化的动力学特征

• 批准号: 10427521
• 负责人: Joseph Nicholas Pucella
• 金额: $ 3.43万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427521
• 关键词: Ablation; Acute Myelocytic Leukemia; Affect; Alleles; Anemia; Antibodies; B lymphoid malignancy; B-Lymphocytes; Blood; Blood Cells; Bone Marrow; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Clinical; Data; Development; Disease; Dysmyelopoietic Syndromes; Dysplasia; Enterobacteria phage P1 Cre recombinase; Event; Feedback; Flow Cytometry; Genetic Transcription; Goals; Hematologic Neoplasms; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Homeostasis; Human; Iatrogenesis; Immunologic Deficiency Syndromes; Impairment; In Situ; KRAS2 gene; KRASG12D; Kinetics; Label; Lesion; Life; Lymphoid; MS4A1 gene; Malignant - descriptor; Mature B-Lymphocyte; Measurement; Mediating; Methods; Modeling; Monoclonal Antibodies; Mus; Mutation; Myelogenous; Myeloproliferative disease; Nature; Oligonucleotides; Oncogenic; Pathologic; Patients; Phenotype; Physiological; Play; Procedures; Process; Recovery; Role; Tamoxifen; Techniques; Time; Transplantation; anti-CD20; clinically relevant; cytopenia; hematopoietic differentiation; hematopoietic stem cell differentiation; high dimensionality; human disease; improved outcome; innovation; interest; leukemia; leukemia treatment; leukemia/lymphoma; mouse model; mutant; novel; novel therapeutics; progenitor; protein biomarkers; rituximab; self-renewal; tool; transcriptomics; young adult

Project Summary Hematopoiesis is the process in bone marrow by which all blood cells are generated throughout organismal life. Normal hematopoiesis is impaired in multiple diseases including anemias, cytopenias, and hematological malignancies such as leukemias and lymphomas. Little is known about the overall dynamics and progenitor hierarchy of steady-state unperturbed hematopoiesis (as opposed to the transplant setting), and how these are affected by oncogenic transformation or iatrogenic insults such as lineage ablation. Our overall goal is to characterize in detail the in situ dynamics of physiological hematopoiesis and progenitor phenotypes at steady- state and during adaptation to hematopoietic disruption. We propose to employ specific labeling and lineage tracing of hematopoietic stem cells (HSC) with cellular indexing of transcriptomes and epitopes by single cell sequencing (CITE-Seq) to accomplish three specific aims. The first is to characterize the intermediate progenitor phenotypes and dynamics in an unbiased manner during steady-state hematopoiesis. In doing so, we will construct a comprehensive and unbiased roadmap of hematopoietic differentiation. The second aim is to investigate adaptation of hematopoiesis to leukemogenic perturbation. And lastly, the third aim is to elucidate hematopoietic adaptation to the clinically relevant procedure of mature hematopoietic cell ablation. The proposed studies will describe for the first time the kinetics of hematopoietic differentiation in a variety of physiological, pathological and iatrogenic settings. To accomplish this goal, we will synergistically integrate cutting-edge techniques in an innovative way. These studies would significantly advance the field of hematology, paving the way for the development of novel therapies for maladies caused by disruption of normal hematopoietic differentiation.

项目摘要 造血是骨髓中的过程，所有血细胞在整个过程中产生 有机体生命正常的造血在多种疾病中受损，包括贫血、血细胞减少和 血液恶性肿瘤，如白血病和淋巴瘤。人们对总体动态知之甚少， 稳态未受干扰造血的祖细胞层次（相对于移植设置），以及如何 这些受到致癌转化或医源性损伤如谱系消除的影响。我们的总体目标是 详细描述稳态时生理造血和祖细胞表型的原位动力学， 状态和适应造血中断期间。我们建议采用特定的标签和血统 单细胞标记转录组和表位追踪造血干细胞 测序（CITE-Seq），以实现三个具体目标。一是对中间祖细胞进行定性 表型和动力学在稳态造血过程中以无偏的方式。为此，我们将 构建一个全面和公正的造血分化路线图。第二个目标是 研究造血对白血病发生干扰适应性。最后，第三个目的是阐明 造血适应成熟造血细胞消融的临床相关程序。拟议 研究将首次描述造血分化在多种生理， 病理和医源性环境。为了实现这一目标，我们将协同整合尖端技术， 技术创新的方式。这些研究将大大推进血液学领域，为血液学的发展铺平道路。 开发用于由正常造血破坏引起的疾病的新疗法的方法 分化