Using spatial, single-cell genomic recording to investigate age-associated clonal hematopoiesis

利用空间单细胞基因组记录研究与年龄相关的克隆造血作用

• 批准号: 10608900
• 负责人: MICHAEL B ELOWITZ
• 金额: $ 54.14万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608900
• 关键词: Age; Aging; Bar Codes; Blood; Blood Cells; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Bone marrow failure; Cell Count; Cells; Clonal Expansion; Clone Cells; Complex; Data; Databases; Diagnosis; Disease; Engineering; Environment; Exposure to; Gene Expression; Genes; Genomics; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemorrhage; Imaging Techniques; In Situ; Individual; Infection; Injury; Knock-out; MPP3 gene; Maps; Memory; Mesenchymal; Methods; Molecular; Mus; Mutagenesis; Mutation; Optics; Positioning Attribute; Recording of previous events; Regenerative Medicine; Research; Resolution; Role; Signal Pathway; Signal Transduction; System; Testing; Variant; Work; age related; aged; bone aging; bone invasion; cell type; cellular imaging; experimental study; imaging modality; improved; intercellular communication; leukemia; leukemia/lymphoma; migration; novel therapeutic intervention; progenitor; stem; stem cells; therapeutic target

Project Summary: Hematopoiesis primarily takes place within the dense milieu of the bone marrow. It is regulated by complex signaling interactions among multiple cell types to maintain a balanced blood pool and to respond to injuries such as bleeding and infection. During aging, hematopoiesis declines and develops clonal dominance, also known as clonal hematopoiesis, where a small number of hematopoietic stem and progenitor cells (HSPCs) produce a disproportionately large amount of blood cells. Clonal hematopoiesis has been associated with various types of hematologic disorders including leukemia. To understand how and why clonal hematopoiesis develops with age, it is crucial to examine the key intercellular communications that regulate hematopoiesis within the bone marrow. This is particularly important because of dramatic age-associated changes to the bone marrow where the cell number substantially decreases and the cell type composition massively shifts, leading to changes in the intercellular signaling network critical for hematopoiesis. Here, we will apply a new genomic recording and imaging technique, MEMOIR (Memory through Enhanced Mutagenesis with Optical In-situ Readout), to analyze how the aging bone marrow environment alters HSPC intercellular signaling and influences clonal hematopoiesis. We will test two opposite hypotheses: (1) clonal hematopoiesis is induced by age-associated changes to the intercellular signaling of HSPCs in the bone marrow; and alternatively (2) clonal hematopoiesis is the result of intrinsic changes in HSPCs that allow them to escape from the control of the intercellular signaling network. We will determine how aging alters the spatial context and intercellular signaling of HSPCs, and influences their clonal expansion. And we will investigate how age-associated spontaneous mutations perturb the spatial context and intercellular signaling of HSPC clonal expansion. Our proposed study will identify the lineage relationships and spatial organization of individual HSPCs as well as their intercellular signaling in the aging bone marrow. Our results can reveal new cellular and molecular players underlying clonal hematopoiesis that could be used as therapeutic targets to control hematopoietic aging and age-related diseases. More generally, this study will provide an experimental and conceptual framework for analyzing spatially defined intercellular communication in hematopoiesis.

项目概要： 造血主要发生在骨髓的致密环境中。它受复杂的调节 多种细胞类型之间的信号相互作用，以维持平衡的血池并对损伤做出反应 比如出血、感染等。在衰老过程中，造血功能下降并发展出克隆优势， 称为克隆造血，其中少量造血干细胞和祖细胞（HSPC） 产生不成比例的大量血细胞。克隆性造血与 各种类型的血液疾病，包括白血病。了解克隆造血的方式和原因 随着年龄的增长，检查调节造血的关键细胞间通讯至关重要 骨髓内。这一点尤其重要，因为骨骼会随着年龄的增长而发生巨大的变化 骨髓中的细胞数量大幅减少，细胞类型组成发生巨大变化，导致 对造血至关重要的细胞间信号网络的变化。在这里，我们将应用新的基因组 记录和成像技术，MEMOIR（通过光学原位增强突变形成的记忆） Readout），分析老化的骨髓环境如何改变 HSPC 细胞间信号传导和 影响克隆造血。我们将检验两个相反的假设：（1）克隆造血是由 骨髓中 HSPC 细胞间信号传导与年龄相关的变化；或者 (2) 克隆 造血是 HSPC 内在变化的结果，这些变化使它们能够逃脱细胞的控制。 细胞间信号网络。我们将确定衰老如何改变空间环境和细胞间信号传导 HSPC，并影响其克隆扩增。我们将研究与年龄相关的自发性 突变扰乱 HSPC 克隆扩张的空间背景和细胞间信号传导。我们提出的研究 将识别单个 HSPC 及其细胞间的谱系关系和空间组织 衰老骨髓中的信号传导。我们的结果可以揭示潜在的新细胞和分子参与者 克隆造血可作为控制造血衰老和年龄相关的治疗靶点 疾病。更一般地说，这项研究将为分析提供一个实验和概念框架 造血过程中空间定义的细胞间通讯。