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: 10386006
• 负责人: Alexandra Zezulin
• 金额: $ 3.42万
• 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/10386006
• 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.

项目概要： 转录因子RUNX1的功能缺失突变经常发生在急性髓性白血病（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的患者 突变易导致炎症性疾病，如哮喘和湿疹。RUNX1突变 并且它们对肿瘤发生的作用也有很好的描述。然而，RUNX1突变对 炎症反应知之甚少。我们的实验室最近证明了RUNX1在 调节小鼠中性粒细胞的炎症反应。泛造血RUNX1缺失激活了一种 致敏中性粒细胞响应Toll样受体过度活化炎性转录程序 4（TLR4）刺激。由于中性粒细胞是骨髓小生境的重要组成部分，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导致 RUNX1突变患者的克隆性造血和白血病风险本提案的目的是 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中性粒细胞前体中的 祖细胞表观基因组，然后繁殖到分化的中性粒细胞，使他们对 TLR4配体。我的建议的第一个目标是检验这个假设。第二个目标是确定是否 RUNX1直接调节中性粒细胞前体中TLR4通路基因的表达，或者如果RUNX1缺失， 其它造血细胞有助于炎性嗜中性粒细胞反应。