Role of the local vascular microenvironment in the bone marrow response to inflammation

局部血管微环境在骨髓炎症反应中的作用

• 批准号: 10451791
• 负责人: Daniel Lucas
• 金额: $ 56.89万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-20 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451791
• 关键词: Architecture; Blood Vessels; Bone Marrow; CSF1 gene; CSF3 gene; Candida albicans; Cell Aging; Cell Lineage; Data; Dendritic Cells; Emergency Situation; Endothelial Cells; Erythropoiesis; Failure; Hematopoiesis; Hematopoietic stem cells; IL1R1 gene; Image; In Situ; Infection; Infection Control; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interleukin-1; Knockout Mice; Listeria monocytogenes; MPP2 gene; MPP3 gene; Macrophage Colony-Stimulating Factor; Marrow; Molecular; Multipotent Stem Cells; Myelogenous; Myelopoiesis; Output; Production; Role; Signal Transduction; Stress; Study models; Testing; Therapeutic Intervention; base; conditional knockout; cytokine; experimental study; granulocyte; in vivo Model; loss of function; monocyte; neutrophil; new therapeutic target; novel; progenitor; response; selective expression; spatiotemporal; stem cell function; stem cells; technique development

Abstract: Bone marrow (BM) inflammation is a driver of hematopoietic stem and progenitor cell (HSPC) aging, transformation, and marrow failure but also indispensable for innate immune responses to infection. The role of the microenvironment in the response to inflammation is incompletely understood. We found that unique subsets of marrow vessels differentially regulate neutrophil or dendritic cell production in respond to inflammation. We want to understand how the local architecture of the microenvironment controls which –and how- HSPC respond to infection/inflammation. We have found that CSF1+ vessels regulate emergency dendritic cell production in response to infection by targeting myeloid dendritic cell progenitors (MDP) whereas IL1R1+ vessels regulate multipotent progenitors and committed granulocyte progenitors in response to IL1. We hypothesize “that the local architecture of the BM vascular microenvironment controls which-and how- HSPC respond to infection/inflammation. Unique subsets of BM vessels are cellular antennas that sense different inflammatory insults and control commitment and differentiation of adjacent HSPC in response to these insults. IL1R1+ and CSF1+ vessels are two examples of these cellular antennas” We will test this hypothesis in three aims. In Aim 1 we will investigate how the different vessels spatially organize hematopoiesis and test the hypothesis that proximity to each vessel dictates which progenitor responds to infection/inflammation. In Aim2 we will investigate the mechanisms through which each type of vessel regulates HSPSC function and differentiation. In Aim 3 we will determine how each type of vessel senses and responds to different types of infection/inflammation and test the hypothesis that each vessel has evolved to sense specific insults.

摘要： 骨髓（BM）炎症是造血干细胞和祖细胞（HSPC）老化的驱动因素， 转化和骨髓衰竭，但也是对感染的先天免疫反应不可或缺的。的作用 对炎症反应的微环境还不完全了解。我们发现， 骨髓血管亚群对中性粒细胞或树突状细胞产生的调节差异 炎症我们想了解微环境的本地架构如何控制哪些-以及 HSPC如何响应感染/炎症。 我们发现，CSF 1+血管通过以下途径调节感染后树突状细胞的产生： 靶向髓样树突状细胞祖细胞（MDP），而IL 1 R1+血管调节多能祖细胞 以及响应于IL 1的定向粒细胞祖细胞。我们假设“当地的建筑 BM血管微环境控制HSPC对感染/炎症的反应和反应方式。独特 BM血管的亚群是细胞天线，其感测不同的炎性损伤并控制定型 以及邻近HSPC对这些损伤的反应的分化。IL 1 R1+和CSF 1+血管是两个 这些蜂窝天线的例子” 我们将从三个方面来检验这一假设。在目标1中，我们将研究不同血管在空间上如何 组织造血，并测试假设，接近每个血管决定哪一个祖细胞 对感染/炎症有反应。在目标2中，我们将研究每种类型的 血管调节HSPSC的功能和分化。在目标3中，我们将确定每种类型的船只如何 感知并响应不同类型的感染/炎症，并测试每个血管具有 进化到能感知特定的侮辱