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Spatial Control of Myeloid Differentiation

骨髓分化的空间控制

基本信息

批准号：
10671625
负责人：
Daniel Lucas
金额：
$ 51.23万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671625
关键词：
Acute Myelocytic Leukemia Adoptive Transfer Anatomy Bone Marrow CSF1 gene CSF3 gene Cells Cessation of life Cues DNMT3a Data Dendritic Cells Development Discontinuous Capillary Disease Distal Emergency Situation Endothelial Cells Endothelium Erythroid Erythropoiesis FLT3 gene FLT3 ligand Failure Hematopoiesis Hematopoietic Homeostasis Image In Situ Location MLL-AF9 Macrophage Macrophage Colony-Stimulating Factor Manuscripts Maps Modeling Molecular Mus Myelogenous Myelopoiesis Normal Cell Output Pathology Pericytes Physiology Production Reporter Role Scheme Signal Transduction Source Stress Structure Testing Therapeutic Intervention cytokine cytopenia experimental analysis experimental study granulocyte in vivo in vivo Model leukemia leukemia initiating cell monocyte mortality mouse genetics neutrophil novel progenitor recruit segregation spatiotemporal stem cells tool transcriptomics

项目摘要

Abstract: Mounting evidence indicates that lineage decisions are controlled by local structures that support differentiation in distinct regions of the bone marrow. Our ability to manipulate hematopoiesis to treat disease has been hampered by our lack of understanding of these anatomical cues. We have found that HPC are regionally organized in the BM and that progenitors and immature cells belonging to the same lineage segregate to different sinusoids. We have also found that there is regional organization to CSF1 production and that specific BM vessels are critical sources of CSF1 that regulate MDP, monocytes and dendritic cells but not HSC or macrophages. The central hypothesis is that different subsets of sinusoids function as assembly lines or hubs that organize and maintain different hematopoietic lineages through the production of lineage-specific cytokines. We want to understand how these cellular assembly lines function in the steady-state and after perturbation by acute myeloid leukemia (AML). We will test this hypothesis in two aims. In Aim 1 we will determine the physiology of these assembly lines using clonal fate mapping in situ; identifying the components of each assembly line; and conditionally deleting specific cytokines from key components of each assembly line. In Aim 2 we will investigate how AML inhibits normal hematopoiesis by perturbing the microenvironment that supports each assembly line.

抽象的：越来越多的证据表明，血统决定是由支持分化的当地结构控制的位于骨髓的不同区域。我们操纵造血来治疗疾病的能力已经由于我们对这些解剖线索缺乏了解而受到阻碍。我们发现 HPC 在 BM 中按区域组织，祖细胞和未成熟细胞属于同一谱系分离到不同的正弦曲线。我们还发现有一个区域组织 CSF1 的产生以及特定的 BM 血管是调节 MDP、单核细胞和树突状细胞，但不是 HSC 或巨噬细胞。中心假设是正弦曲线的不同子集作为装配线或枢纽，通过组织和维持不同的造血谱系谱系特异性细胞因子的产生。我们想了解这些细胞装配线如何在稳态和急性髓系白血病（AML）扰动后。我们将从两个目标来检验这个假设。在目标 1 中，我们将确定这些装配线的生理学使用原位克隆命运图谱；识别每条装配线的组件；并有条件删除来自每条装配线关键部件的特定细胞因子。在目标 2 中，我们将研究 AML 如何抑制通过扰乱支持每条装配线的微环境来维持正常的造血功能。