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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要在正常哺乳动物发育过程中，造血系统经历受控成熟。驾驶在此过程中，造血干细胞和祖细胞 (HSPC) 的定义发生了巨大的转变特征。这些包括自我更新、谱系偏差、分化细胞库的变化产生的，甚至可能是效力。这个过程在特定年龄的生物学中具有至关重要的意义血液疾病、造血干细胞移植、正常衰老以及为患者设计的努力用于治疗的特定造血细胞。我们和其他人的工作涉及高度发育状态规范中保守的异时性Lin28b/let-7 microRNA调控轴 HSPC。我们已经证明，Lin28b 对 let-7 microRNA 生物发生的抑制定义了红细胞- 胎儿骨髓祖细胞输出偏向，而发育过程中 Lin28b 表达下调到成年期，成熟骨髓具有强大的骨髓生成特征。初步数据该提案支持新兴的范式，即个体 CMP 具有单一的血统命运它们的起源（即单能性）是由它们的转录状态决定的。该提案测试了假设在造血系统的成熟过程中，HSPC 群体以它们的方式进化。异质单细胞组成，以实现自我更新中发育所必需的变化，效力和谱系限制分支点； Lin28b/let-7 轴在调节中起着核心作用这个过程。该提案的具体目标是：1）研究 Lin28b/let-7 在调节随着体内发育时间的推移，谱系效力发生变化； 2）直接连接Activity Lin28b/let-7 轴到谱系结果； 3) 评估 Lin28b/let-7 调节的机制指定 HSPC 发育状态的基因调控网络。我目前是波士顿儿童医院小儿血液肿瘤科的临床研究员。我有提出了一个五年职业发展计划，该计划将建立在我的临床背景基础上儿科血液学以及我之前在发育性造血方面的研究经验建立了一个在主要学术中心担任独立调查员/医生科学家的职业生涯。合并下 George Q. Daley 博士（医学博士、哲学博士）的指导Benjamin L. Ebert 博士（医学博士、哲学博士）在以下领域树立了领导者的地位：在正常和患病血液学的研究中，我建议对基本原理进行严格的研究造血祖细胞正常发育成熟的机制。 K08奖将为我提供必要的受保护时间来执行拟议的学习和职业发展五年期限内的计划。