Investigating the heterogeneity and coordination of hematopoietic stem cells

项目总结： 干细胞在生物体的一生中补充组织和器官，并可以在受伤后修复损伤。 干细胞具有自我更新和分化的特殊能力，有望给医学带来革命性的变化。 为了开发更好和更安全的干细胞疗法，提高对干细胞的理解至关重要。 细胞调节。关于干细胞调节的大部分知识来自于研究 聚集数千到数百万个干细胞的行为。然而，最近的研究表明，个人 在小鼠和人类中，造血干细胞(HSC)的表现都有很大的不同。 这些新发现的细胞间差异为研究HSC提供了令人兴奋的新机会 监管。然而，它们也带来了难以解决的重大技术挑战 传统的方法。拟议的研究计划将使用一种新的系统生物学方法。 与定量单细胞分析相结合，确定潜在的细胞和分子机制 HSC的异质性和协调性及其对衰老和糖尿病发病机制的影响 血液病。许多血液病--如骨髓衰竭、骨髓增生性疾病 疾病、骨髓增生异常综合征和其他与年龄相关的造血问题-由罕见的 细胞。拟议的研究计划将绘制这些疾病的确切发病机制图，并确定 利用新开发的单细胞跟踪和分子图谱技术获得疾病创立者克隆和基因 技术。随着这些技术的进步，拟议中的研究还将产生新的基础 了解血液再生，这是骨髓移植的基础。长期目标 是应用从拟议的基础研究中获得的知识来控制血液再生 治疗应用，早期发现白血病和其他克隆性疾病，并有效治疗疾病 使用先进的干细胞疗法。

Project Summary: Stem cells replenish tissues and organs over an organism’s lifetime and can repair damage after injury. With their special capacities for self-renewal and differentiation, stem cells promise to revolutionize medicine. To develop better and safer stem cell therapies, it is critically important to improve the understanding of stem cell regulation. Most of the knowledge about stem cell regulation comes from studies that investigate the aggregate behaviors of thousands to millions of stem cells. However, recent studies suggest that individual hematopoietic stem cells (HSCs) behave substantially differently from one another in both mice and humans. These newly discovered inter-cellular differences present exciting new opportunities for studying HSC regulation. However, they also present significant technical challenges that are difficult to address with conventional approaches. The proposed research program will use a novel systems biology approach combined with quantitative single-cell analysis to determine the cellular and molecular mechanisms underlying HSC heterogeneity and coordination, as well as their influences on aging and the pathogenesis of hematopoietic diseases. Many hematopoietic diseases—such as bone marrow failure, myeloproliferative disorders, myelodysplastic syndromes and other age-associated hematopoietic problems—are initiated by rare cells. The proposed research program will map the precise pathogenesis of these diseases and identify disease founder clones and genes using newly developed single cell tracking and molecular profiling technologies. With these technical advances, the proposed research will also produce new fundamental knowledge about blood regeneration, the foundation of bone marrow transplantation. The long-term objective is to apply the knowledge obtained from the proposed basic research to control blood regeneration for therapeutic use, to detect leukemia and other clonal diseases at early stages, and to effectively treat diseases with advanced stem cell therapies.