Age-specific differentiation of multipotent progenitors

多能祖细胞的年龄特异性分化

基本信息

批准号：
10548221
负责人：
Robert Grant Rowe
金额：
$ 13.28万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-07 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10548221
关键词：
Acceleration Adolescent Adult Affect Age Aging Anatomy Birth Blood Cell Compartmentation Cell Maturation Cells Child Childhood Chromatin Clinical Collection Complex Data Data Set Development Disease Down-Regulation Embryo Enhancers Epigenetic Process Erythroid Erythroid Progenitor Cells Family Foundations Future Gene Expression Gene Silencing Genomics Goals Hematological Disease Hematopoiesis Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic System Hematopoietic stem cells Investigation Kinetics Life Location Lymphoid Lymphopoiesis Maintenance MicroRNAs Molecular Multipotent Stem Cells Mus Myelogenous Organism Output Pediatric Hematologist Physiological Polycomb Pregnancy Process RNA-Binding Proteins Reader Regulation Regulator Genes Repression Repressor Proteins Research Research Support Role Stem cell transplant System Testing Time Transcript Work blood formation cell behavior chromatin remodeling design experience fetal frontier hematopoietic stem cell self-renewal insight neonate novel postnatal prenatal progenitor programs promoter recruit self-renewal stem cell function young adult

项目摘要

PROJECT SUMMARY/ABSTRACT The foundation of this project is based on the clinical observation that adults and children are affected by different blood disorders, many of which show typical age biases. Accumulating evidence supports the notion that the scripted changes that occur normally in the hematopoietic system during development and aging create transient, age-specific hematopoietic substrates in which these diseases develop. The blood forming system undergoes a controlled maturation process wherein the prioritized lineage outputs, mechanisms of lineage restriction, and rates of hematopoietic stem cell (HSC) self-renewal change from early development through maturation of the organism. Postnatally, as the hematopoietic system ages, these changes continue with a progressive myeloid bias and further diminishment of HSC self-renewal. These temporal changes in the mechanisms of blood formation appear to be regulated both intrinsically and extrinsically, as both the anatomic location and cellular composition of the hematopoietic microenvironment change with time in concert with the function of HSCs. Our prior K08-supported research has identified a novel potential mechanism of epigenetic control of the transition from the transient, juvenile state of hematopoiesis to mature adult hematopoiesis. Here, we will investigate molecular mechanisms regulating the shifting lineage biases that occurs during hematopoietic maturation.

项目概要/摘要该项目的基础是基于对成人和儿童受到影响的临床观察不同的血液疾病，其中许多表现出典型的年龄偏差。越来越多的证据支持这一观点造血系统在发育和衰老过程中正常发生的脚本化变化产生短暂的、年龄特异性的造血基质，这些疾病在其中发生。血液形成系统经历一个受控的成熟过程，其中优先的谱系输出、机制谱系限制以及早期发育中造血干细胞 (HSC) 自我更新率的变化通过有机体的成熟。出生后，随着造血系统老化，这些变化仍在继续伴有进行性骨髓偏向和 HSC 自我更新的进一步减弱。这些暂时的变化血液形成的机制似乎受到内在和外在的调节，因为解剖学造血微环境的位置和细胞组成随时间而变化，与 HSC 的功能。我们之前 K08 支持的研究已经确定了表观遗传的一种新的潜在机制控制从短暂的幼年造血状态到成熟的成年造血状态的转变。在这里，我们将研究调节谱系偏差发生的分子机制。造血成熟。