Project 1 - Molecular and cellular determinants of hematopoietic clonal expansion

项目总结 人类的造血系统是由数十万人自我更新维持的。 造血干细胞和多能祖细胞。最近，大规模的基因研究揭示了 健康个体血细胞中体细胞克隆性突变的流行，这个过程被称为 克隆性造血。单个造血细胞携带CH-1的机制研究进展 相关突变的扩展是以正常突变为代价的，这是一个主要问题 对CH相关并发症患者的治疗和监测的启示。另一个知之甚少的人 CH的一个方面是它的不完全外显。虽然据推测，大多数人到50岁时将拥有 在他们长寿的造血祖细胞中积累了这些突变之一，克隆度 人口的扩张是千差万别的。细胞和分子决定因素 这一范围的克隆行为尚不清楚。我的实验室使用了高分辨率的蜂窝条形码 发现造血祖细胞和干细胞表现出显著异质性的技术 他们对CH相关突变的功能反应。我们的分析还发现了一些 表现出高度竞争的克隆的特征的基因。基于这些数据，我们在这里的项目 旨在了解只有部分造血祖细胞的分子机制 获得并保持竞争优势。此外，我们的方法将利用小说 与生理相关的CH小鼠模型，其中突变可定向到干细胞或祖细胞 车厢。我们在这里的努力将得到最先进的基因组和功能工具的推动 独一无二地适用于描述单细胞水平上的异质性。成功完成了 该项目的目的将为克隆优势相关状态的机制提供新的见解。 与CH.最后，我们的工作可能会确定可操作的目标来操纵克隆竞争。

PROJECT SUMMARY The human hematopoietic system is maintained by a pool of hundreds of thousands self-renewing hematopoietic stem cells and multipotent progenitor cells. Recently, large genetic studies have revealed the prevalence of somatic, clonal mutations, in blood cells of healthy individuals, a process referred as clonal hematopoiesis (CH). The mechanisms by which a single hematopoietic cell carrying a CH- related mutation expands at the expense of its normal counterparts is a major question with implications to treat and monitor patients with CH-related complications. Another poorly understood aspect of CH is its incomplete penetrance. While it is speculated that most humans by age 50 will have accumulated one of these mutations in their long-lived hematopoietic progenitors, the degree of clonal expansion among the population is tremendously varied. The cellular and molecular determinants of this range of clonal behaviors are unclear. My lab has utilized high-resolution cellular barcoding technologies to find that hematopoietic progenitor and stem cells exhibit remarkable heterogeneity in their functional response to CH-associated mutations. Our analyses have also identified a number of genes that characterizes the clones exhibiting hyper-competition. Based on these data, our project here aims to understand the molecular mechanisms by which only a subset of hematopoietic progenitors gains and maintains a competitive advantage. Additionally, our approach will take advantage of novel physiologically relevant mouse models of CH where mutations can be directed to stem or progenitor cell compartments. Our efforts here will be facilitated by state-of-the-art genomic and functional tools uniquely suited to characterize heterogeneity at the single cell level. Successful accomplishment of the aims of this project will provide new insight into the mechanisms of clonal dominance in states associated with CH. Finally, our work will potentially identify actionable targets to manipulate clonal competition.