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: