Role of the Lin28b/let-7 axis in the maturation of hematopoietic progenitor cells

Lin28b/let-7轴在造血祖细胞成熟中的作用

• 批准号: 9370932
• 负责人: Robert Grant Rowe
• 金额: $ 13.2万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9370932
• 关键词: Adult; Affect; Age; Automobile Driving; Award; Biogenesis; Biology; Bone Marrow; Boston; Cell Differentiation process; Cell Ontogeny; Cell Separation; Cells; Characteristics; Clinical; Data; Derivation procedure; Development; Development Plans; Disease; Doctor of Medicine; Doctor of Philosophy; Down-Regulation; Embryo; Engineering; Erythroid; Erythroid Cells; Family; Fetal Liver; Fibronectins; Foundations; Future; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic Enhancer Element; Genetic Transcription; Genetic Translation; Goals; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Hematopoietic stem cells; Heterogeneity; Individual; Investigation; Mature Bone; Mediating; Mentorship; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Analysis; Mus; Myelogenous; Myelopoiesis; Outcome; Output; Pathway interactions; Patients; Pediatric Hematology; Pediatric Hospitals; Phenotype; Physicians; Play; Pluripotent Stem Cells; Population; Process; Production; Property; Publishing; RNA Splicing; RNA-Binding Proteins; Regulation; Regulator Genes; Reporter; Repression; Research; Research Personnel; Role; Scientist; Signal Transduction; Source; Specific qualifier value; Stem cells; Testing; Time; Tissues; Transcriptional Regulation; Work; base; career; career development; experience; fetal; in vivo; indexing; insight; next generation; normal aging; novel; oncology; population based; progenitor; programs; self-renewal; single cell analysis; transcription factor; transcriptome sequencing

PROJECT SUMMARY During normal mammalian development, the hematopoietic system undergoes controlled maturation. Driving this process, hematopoietic stem and progenitor cells (HSPCs) execute dramatic transitions in their defining characteristics. These include changes in self-renewal, lineage biases, repertoires of differentiated cells produced, and possibly even potency. This process is of critical significance in the biology of age-specific blood disorders, hematopoietic stem cell transplantation, normal aging, and efforts to engineer of patient- specific hematopoietic cells for use in therapy. Our work and that of others has implicated the highly conserved heterochronic Lin28b/let-7 microRNA regulatory axis in specification of the developmental state of HSPCs. We have shown that repression of the biogenesis of let-7 microRNAs by Lin28b defines erythroid- biased fetal myeloerythroid progenitor output, while downregulation of Lin28b expression during development to adulthood permits the robust myelopoiesis characteristic of the mature bone marrow. The Preliminary Data in this proposal supports the emerging paradigm that individual CMPs are imbued with a single lineage destiny at their genesis (i.e., unipotency) that is dictated by their transcriptional state. This proposal tests the hypothesis that during maturation of the hematopoietic system, populations of HSPCs evolve in their heterogeneous single cell composition in order to effect developmentally necessary changes in self-renewal, potency, and lineage restricting branch points; and that the Lin28b/let-7 axis plays a central role in regulating this process. The Specific Aims of this proposal are to: 1) investigate the role of Lin28b/let-7 in regulating the changes in lineage potency that occur over developmental time in vivo; 2) directly connect the activity of the Lin28b/let-7 axis to lineage outcomes; and 3) evaluate the mechanisms by which Lin28b/let-7 modulates the gene regulatory networks that specify developmental state in HSPCs. I am currently a clinical fellow in Pediatric Hematology-Oncology at Boston Children's Hospital. I have proposed a five-year career development plan that will build upon the foundation of my clinical background in Pediatric Hematology as well as my prior research experience in developmental hematopoiesis to establish a career as an independent investigator/physician-scientist at a major academic center. Under the combined mentorship of Dr. George Q. Daley, M.D., Ph.D. and Dr. Benjamin L. Ebert, M.D., Ph.D., established leaders in research in normal and diseased hematology, I propose rigorous investigation into the fundamental mechanisms underlying normal developmental maturation of hematopoietic progenitor cells. The K08 award will provide me with the necessary protected time to execute the proposed studies and career development plan within the five-year time frame.

项目摘要 在正常的哺乳动物发育期间，造血系统经历了控制的成熟。驾驶 这个过程，造血茎和祖细胞（HSPC）在其定义中执行戏剧性过渡 特征。这些包括自我更新，谱系偏见的变化，分化细胞的曲目 产生，甚至可能是效力。这个过程在特定年龄的生物学中至关重要 血液疾病，造血干细胞移植，正常衰老以及为患者设计的努力 特异性造血细胞用于治疗。我们的工作和他人的工作牵涉到高度的 保守的杂化LIN28B/LET-7 microRNA调节轴，规范的发育状态 HSPC。我们已经表明，lin28b对let-7 microRNA的生物发生抑制，定义了红斑 - 有偏见的胎儿骨髓性刺头祖细胞输出，而发育过程中LIN28B表达的下调 成年允许成熟的骨髓的强大骨髓骨髓特征。初步数据 在此提案中，支持单个CMP的新兴范式充满了单个血统命运 在其起源（即独立性）中，其转录状态决定了。该建议测试 假设在造血系统成熟期间，HSPC的种群在其中进化 异质的单细胞组成，以实现自我更新的发展必要变化， 效力和血统限制分支点； lin28b/let-7轴在调节中起着核心作用 这个过程。该提案的具体目的是：1）研究LIN28B/LET-7在调节该调节中的作用 体内发育时间内发生的谱系效力的变化； 2）直接连接 lin28b/let-7轴至谱系结果； 3）评估LIN28B/Let-7调节的机制 在HSPC中指定发育状态的基因调节网络。 我目前是波士顿儿童医院的儿科血液肿瘤学临床研究员。我有 提出了一个五年的职业发展计划，该计划将基于我的临床背景的基础 小儿血液学以及我先前在发育造血的研究经验 在一个主要学术中心担任独立研究员/医师科学家的职业。在总和下 医学博士George Q. Daley博士的指导以及Benjamin L. Ebert博士，医学博士，博士学位 关于正常和患病血液学的研究，我提出了对基本的严格研究 造血祖细胞正常发育成熟的基础机制。 K08奖 将为我提供必要的受保护时间来执行拟议的研究和职业发展 计划在五年的时间范围内。