Mechanisms of granulocyte homeostasis

粒细胞稳态机制

基本信息

批准号：
9263013
负责人：
H. LEIGHTON GRIMES
金额：
$ 39万
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 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9263013
关键词：
Alleles Bioinformatics Biological Biology Bone Marrow Cells Cessation of life Clinical Complement Complex DNA Sequence Alteration Data Dysmyelopoietic Syndromes Extravasation Failure Feedback Foundations Gene Expression Profile Genes Genetic Genetic Transcription Granulopoiesis Growth Factor Half-Life Hematopoietic Heterogeneity Homeostasis Human IFN consensus sequence binding protein Immune Individual Infection Investigation Knowledge Marrow Mediating Minority Modernization Molecular Mus Mutation Myelogenous Myeloproliferative disease Neonatal Neutropenia Neutrophilia Patients Pattern Phenotype Process Production Repression Risk Sampling Stress Sum Time Tissues Transcriptional Regulation Work cytokine experimental study gain of function genome sequencing granulocyte gut microbiome in vivo insight loss of function man monocyte mouse model neutrophil progenitor programs public health relevance single cell analysis transcription factor transcriptome transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Understanding 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 (neutrophilia, myeloproliferative disorders). Current knowledge illustrates many factors that can modify granulocyte versus monocyte production; however, we still do not understand a fundamental question: which specific factors control the granulocyte-monocyte lineage decision during homeostatic production in vivo? To discern the transcriptional network underlying the binary fate decision between neutrophil granulocyte and monocyte lineage decisions as they occur at steady state (homeostatic control), we have performed single-cell RNA-seq on bone-marrow granulocyte-monocyte progenitors (GMP). Our bioinformatic analyses reveal a varied, but coherent spectrum of gene expression patterns in individual murine GMPs. The majority of cells could be clustered into ones expressing either granulocytic or monocytic genes, suggesting that they were primed for lineage determination. A minority of GMPs expressed a mixed-lineage pattern of genes. Deeper analyses of the single-cell data implicate the repression of a key requisite factor for monopoiesis in mice and man (Irf8) by a key requisite factor for granulopoiesis in mice and man (Gfi1) as the central mechanism for homeostatic control of the granulocyte-monocyte lineage decision in vivo. We propose to determine the transcriptional program underlying granulocyte-monocyte lineage fate decisions during homeostasis, and then define the impact of severe congenital neutropenia (SCN)-associated mutations on transcriptional control of granulopoiesis in mice and man. We expect to delineate a cross-species transcriptional signature of granulopoiesis, and define the impact of neutropenic stress.

描述（由申请人提供）：了解粒细胞稳态至关重要，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会导致严重的组织损伤和死亡（中性粒细胞增多症、骨髓增殖性疾病）。许多因素可以改变粒细胞与单核细胞的产生；然而，我们仍然不明白一个基本问题：哪些特定因素控制稳态产生过程中的粒细胞-单核细胞谱系决定。为了辨别中性粒细胞和单核细胞谱系决定在稳态（稳态控制）下发生的二元命运决定背后的转录网络，我们对骨髓粒细胞-单核细胞祖细胞进行了单细胞 RNA 测序（GMP）我们的生物信息学分析揭示了个体小鼠 GMP 中各种但一致的基因表达模式，大多数细胞可以聚集成表达粒细胞或单核细胞的细胞。基因，表明少数 GMP 表达了基因的混合谱系模式。小鼠和人类粒细胞生成的关键必要因子（Gfi1）作为体内粒细胞-单核细胞谱系决定的稳态控制的中心机制我们建议确定转录。细胞稳态过程中粒细胞-单核细胞谱系命运决定的基础程序，然后定义严重先天性中性粒细胞减少症（SCN）相关突变对小鼠和人类粒细胞生成转录控制的影响，以及我们期望描绘粒细胞生成的跨物种转录特征。定义中性粒细胞减少应激的影响。