Determining how RUNX1 regulates the inflammatory response in neutrophils

确定 RUNX1 如何调节中性粒细胞的炎症反应

• 批准号: 10731054
• 负责人: Alexandra Zezulin
• 金额: $ 0.88万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10731054
• 关键词: Acute Myelocytic Leukemia; Asthma; Binding; Binding Sites; Blood Platelets; Bone Marrow; Bone Marrow Cells; Cell Line; Cell Transplantation; Cell surface; Cells; Cellular Assay; ChIP-seq; Chromatin; Chronic; Clinical; Data; Defect; Disease; Dysmyelopoietic Syndromes; Eczema; Enhancers; Epigenetic Process; Familial Platelet Disorder; Gene Expression; Genes; Genetic Transcription; Germ-Line Mutation; Goals; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hypersensitivity; Inflammation; Inflammatory; Inflammatory Response; Inherited; Knock-out; Knockout Mice; Ligands; Link; Lipopolysaccharides; Lung; Lymphoblastic Leukemia; Lymphocyte; Mediating; Mus; Mutate; Mutation; Myelogenous; Myeloproliferative disease; Pathway interactions; Patients; Phenotype; Platelet Activation; Play; Population; Production; Proteins; RUNX1 gene; Reporting; Risk; Role; Signal Pathway; Signal Transduction; Signaling Protein; Susceptibility Gene; TLR4 gene; TNF gene; Testing; Thrombocytopenia; chemokine; cohort; cytokine; epigenome; experimental study; granulocyte-monocyte progenitors; in vivo; leukemia; loss of function mutation; mouse model; neutrophil; prevent; progenitor; programs; response; stem cells; transcription factor; transcriptomics; tumorigenesis

PROJECT SUMMARY: Loss of function mutations in the transcription factor RUNX1 often occur in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Patients carrying inherited RUNX1 mutations are predisposed to developing clonal hematopoiesis, myelodysplastic syndrome, and leukemia. Interestingly, patients with inherited RUNX1 mutations are predisposed to developing inflammatory disorders such as asthma and eczema. RUNX1 mutations and their contributions to oncogenesis are well described. However, the broader effects of RUNX1 mutations on inflammatory responses are poorly understood. Our lab recently demonstrated that RUNX1 has a significant role in regulating inflammatory responses in mouse neutrophils. Pan- hematopoietic RUNX1 loss activated an inflammatory transcriptional program that primed neutrophils to hyperactivate in response to toll-like receptor 4 (TLR4) stimulation. Since neutrophils are an important component of the bone marrow niche, we hypothesize that increased inflammatory cytokine and chemokine production by neutrophils may contribute to the elevated risk of clonal hematopoiesis and leukemia in patients with RUNX1 mutations. The goal of this proposal is to understand the mechanisms by which RUNX1 regulates inflammation in neutrophils. I hypothesize that alterations in the TLR4 signaling pathway are established in a neutrophil precursor by an alteration in the progenitor epigenome that is then propagated to differentiated neutrophils, causing them to hyper-respond to TLR4 ligands. The first goal of my proposal is to test this hypothesis. The second goal is to determine whether RUNX1 directly regulates the expression of TLR4 pathway genes in neutrophil precursors, or if RUNX1 loss in other hematopoietic cells contributes to the inflammatory neutrophil response.

项目总结： 转录因子RUNX1的功能缺失突变常发生在急性髓系白血病(AML)和 骨髓增生异常综合征(MDS)。携带遗传性RUNX1突变的患者更容易发生 克隆性造血、骨髓增生异常综合征和白血病。有趣的是，遗传性RUNX1患者 突变容易发展成炎症性疾病，如哮喘和湿疹。RUNX1突变 它们在肿瘤发生中的作用也得到了很好的描述。然而，RUNX1突变的更广泛的影响 人们对炎症反应知之甚少。我们的实验室最近证明了RUNX1具有重要的作用 调节小鼠中性粒细胞的炎症反应。泛造血RUNX1丢失激活了AN 炎症转录程序启动中性粒细胞对Toll样受体的高度激活 (TLR4)刺激。由于中性粒细胞是骨髓巢的重要组成部分，我们假设 中性粒细胞产生的炎性细胞因子和趋化因子的增加可能是导致 RUNX1突变患者发生克隆性造血和白血病的风险。这项提议的目标是 了解RUNX1调节中性粒细胞炎症的机制。我假设 TLR4信号通路的改变是通过改变TLR4信号通路在中性粒细胞前体中建立的 祖细胞表观基因组，然后被传播到分化的中性粒细胞，使他们对 TLR4配体。我提议的第一个目标是检验这一假设。第二个目标是确定是否 RUNX1直接调节TLR4途径基因在中性粒细胞前体细胞中的表达，或者如果RUNX1在中性粒细胞前体中丢失 其他造血细胞参与炎症性中性粒细胞反应。