Mechanisms of granulocyte homeostasis

粒细胞稳态机制

• 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
• 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

 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（由适用提供）：了解粒细胞体内平衡至关重要，因为产生太少的粒细胞会导致感染风险增加（中性粒细胞），而产生过多的粒细胞会导致严重的组织损害和死亡（中性粒细胞增生，骨髓增生性疾病）。当前的知识说明了许多可以改变粒细胞与单核细胞产生的因素。但是，我们仍然不了解一个基本问题：哪些特定因素控制体内体内稳态生产期间粒细胞 - 单细胞谱系的决策？为了辨别中性粒细胞粒细胞和单核细胞谱系在稳态（稳态控制）时的二元命运决定基础的转录网络，我们已经在骨髓粒细胞 - 单细胞单核细胞 - 单位细胞祖细胞（GMP）上进行了单细胞RNA-Seq。我们的生物信息学分析显示，单个鼠GMP中基因表达模式的多样化但相干。大多数细胞可以聚集成表达粒细胞或单核细胞基因的细胞，表明它们是用于谱系测定的。少数GMP表示基因的混合细胞模式。对单细胞数据的更深入的分析暗示，通过小鼠和人（GFI1）的关键必要因素（GFI1），单型虫子在小鼠和人（IRF8）中的关键因素的表达表示是对粒细胞 - 可调性线条决策的稳态控制的核心机制。我们建议确定体内稳态期间粒细胞 - 单位细胞谱系的命运决定的转录程序，然后确定与小鼠和男人中严重的先天性中层（SCN）相关突变对颗粒细胞转录控制的影响。我们希望描绘粒细胞的跨物种转录特征，并定义中性应激的影响。