Mechanisms of granulocyte homeostasis

粒细胞稳态机制

基本信息

批准号：
10609865
负责人：
H. LEIGHTON GRIMES
金额：
$ 57.52万
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：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10609865
关键词：
ATAC-seq Address Binding Biological Assay CSF3 gene Cell model Cell surface Cells Cessation of life ChIP-seq Chromatin Clinical Complex Data Data Set Development Disease Enhancers Epitopes Event Extravasation GFI1 gene Gene Expression Generations Genes Genetic Genetic Transcription Genomics Granulopoiesis Half-Life Hematopoietic Hi-C Homeostasis Host Defense Human Immune Immune System Diseases Immune signaling Innate Immune System Investigation Link Macrophage Marrow Mediating Modeling Molecular Molecular Profiling Mus Mutation Myelogenous Myeloid Cells Myeloproliferative disease Natural Immunity Neonatal Neutropenia Neutrophilia Normal Cell Pathway interactions Patients Process Production Role Sampling Specific qualifier value Tissues Transcriptional Regulation Variant Visit bioinformatics tool cell type cytokine differential expression gene regulatory network genetic variant granulocyte gut microbiome human model infection risk innate immune function insight microbial microbial colonization microbiome monocyte mouse model mutant neutrophil novel progenitor programs promoter receptor repaired single-cell RNA sequencing transcription factor transcription regulatory network transcriptome

项目摘要

SUMMARY Understanding the cellular and molecular processes underlying granulocyte homeostasis is crucial because producing too few granulocytes results in increased risk for infection (neutropenia), while producing too many granulocytes can result in severe tissue damage and death (myeloproliferative disorders). To delineate the molecular mechanisms underlying homeostatic neutrophil production, we previously delineated hierarchical genomic and regulatory states culminating in neutrophil or macrophage specification. Myeloid cells undergoing lineage specification traverse successive states of mixed-lineage gene expression dictated by antagonistic transcriptional programs (HSCP vs. myeloid progenitor, then Irf8 vs. Gfi1) that culminate in generation of neutrophil or monocyte precursors. Using neutropenia-patient-derived mutations in the GFI1 transcription factor, we generated mouse models of congenital neutropenia. To delineate the molecular mechanisms underlying homeostatic neutropenia and innate immune dysfunction in these mice, we first captured normal cell states encompassing neutrophil specification and commitment, then built a computational approach to assign neutropenia-model cells to normal cell states and assess cell-state specific variation in gene expression. Surprisingly, the majority of differentially expressed GFI1-target genes are sequentially altered as cells traverse successive states. Underscoring these cell state-specific insights, genetic rescue impacts specification but not innate immunity programmed during commitment. Here, we propose to provide regulatory insight explaining this finding; defining altered Gfi1-mutant binding and stage-specific open chromatin. Next, we will determine how neutrophil defense functions are programmed during commitment, and how that fails in humans and mice with neutropenia. Finally, we will revisit the gene regulatory network underlying homeostatic neutrophil versus macrophage specification in the context of establishing neutrophil homeostasis through waves of neonatal gut microbiome colonization. We propose that mouse modeling of mutations identified in neutropenic patients can be exploited to reveal the essential pathobiology of neutropenia, and to dissect mechanisms underlying normal innate immune function and the establishment of granulocyte homeostasis. 1

概括了解粒细胞稳态的细胞和分子过程至关重要，因为产生太少的粒细胞会导致感染风险增加（中性粒细胞减少症），而产生太多的粒细胞粒细胞可导致严重的组织损伤和死亡（骨髓增殖性疾病）。来划定中性粒细胞稳态产生的分子机制，我们之前描述了分层基因组和调节状态最终导致中性粒细胞或巨噬细胞规范。骨髓细胞正在经历谱系规范遍历由拮抗作用决定的混合谱系基因表达的连续状态转录程序（HSCP 与骨髓祖细胞，然后 Irf8 与 Gfi1）最终产生中性粒细胞或单核细胞前体。在 GFI1 转录中使用中性粒细胞减少症患者衍生的突变因素，我们建立了先天性中性粒细胞减少症的小鼠模型。描述分子机制在这些小鼠中潜在的稳态中性粒细胞减少症和先天免疫功能障碍，我们首先捕获了正常的细胞状态包括中性粒细胞的规格和承诺，然后建立了一种计算方法将中性粒细胞减少症模型细胞分配至正常细胞状态并评估细胞状态特异性基因变异表达。令人惊讶的是，大多数差异表达的 GFI1 靶基因依次改变为细胞遍历连续的状态。强调这些细胞状态特定的见解、基因拯救的影响规范，但不是在承诺期间编程的先天免疫。在此，我们建议提供监管解释这一发现的见解；定义改变的 Gfi1 突变体结合和阶段特异性开放染色质。接下来，我们将决定中性粒细胞防御功能在承诺期间如何编程，以及如何失败患有中性粒细胞减少症的人和小鼠。最后，我们将重新审视体内平衡的基因调控网络在通过建立中性粒细胞稳态的背景下中性粒细胞与巨噬细胞的规范新生儿肠道微生物定植浪潮。我们建议对小鼠中发现的突变进行建模中性粒细胞减少症患者可用于揭示中性粒细胞减少症的基本病理学，并剖析正常先天免疫功能和粒细胞稳态建立的机制。 1

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Granulocyte-Monocyte Progenitors and Monocyte-Dendritic Cell Progenitors Independently Produce Functionally Distinct Monocytes.

DOI：
10.1016/j.immuni.2017.10.021
发表时间：
2017-11-21
期刊：
Immunity
影响因子：
32.4
作者：
Yáñez A;Coetzee SG;Olsson A;Muench DE;Berman BP;Hazelett DJ;Salomonis N;Grimes HL;Goodridge HS
通讯作者：
Goodridge HS

GM-CSF Programs Hematopoietic Stem and Progenitor Cells During Candida albicans Vaccination for Protection Against Reinfection.

DOI：
10.3389/fimmu.2021.790309
发表时间：
2021
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Bono C;Guerrero P;Jordán-Pla A;Erades A;Salomonis N;Grimes HL;Gil ML;Yáñez A
通讯作者：
Yáñez A

A primer on single-cell genomics in myeloid biology.

DOI：
10.1097/moh.0000000000000623
发表时间：
2021-01
期刊：
CURRENT OPINION IN HEMATOLOGY
影响因子：
3.2
作者：
Ferchen, Kyle;Song, Baobao;Leighton Grimes, H.
通讯作者：
Leighton Grimes, H.

A guide to choosing fluorescent protein combinations for flow cytometric analysis based on spectral overlap.

DOI：
10.1002/cyto.a.23360
发表时间：
2018-05
期刊：
Cytometry. Part A : the journal of the International Society for Analytical Cytology
影响因子：
0
作者：
Kleeman B;Olsson A;Newkold T;Kofron M;DeLay M;Hildeman D;Grimes HL
通讯作者：
Grimes HL

Aging Human Hematopoietic Stem Cells Manifest Profound Epigenetic Reprogramming of Enhancers That May Predispose to Leukemia.