MDS-Associated Spliceosome Mutations Regulate Host Defense

MDS 相关剪接体突变调节宿主防御

• 批准号: 10097711
• 负责人: Scott Alper
• 金额: $ 55.53万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-11 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10097711
• 关键词: Accounting; Bacteria; Bacterial Infections; Blood Cells; Cause of Death; Cell Differentiation process; Cell physiology; Cells; Cessation of life; Chemotaxis; Clinical Data; Colorado; Defect; Disease; Dysmyelopoietic Syndromes; Engineering; Exhibits; Gene Mutation; Genes; Goals; Hematologic Neoplasms; Hematopoietic stem cells; Host Defense; Human; Immune System Diseases; Immune signaling; Infection; Lead; Link; Mus; Mutate; Mutation; Myeloid Cells; Patient risk; Patients; Phagocytosis; Play; Predisposition; Production; Role; SRSF2 gene; Sampling; Signal Pathway; Spliced Genes; Spliceosomes; Technology; Testing; Toll-like receptors; Universities; base; cell type; clinical practice; genomic data; in vivo; infection rate; infection risk; macrophage; mouse model; mutant; neutrophil; next generation sequencing; patient health information; programs; risk stratification

ABSTRACT Myelodysplastic Syndrome (MDS) is a hematopoietic stem cell disorder characterized by myeloid cell differentiation defects and dysplastic blood cell production. The majority of MDS patients die of disease related causes, with infection or infectious complications being the most common cause. While it is known that myeloid cells exhibit functional defects in MDS patients, the extent and cause of these defects remain unclear and the corresponding effects on host defense have received limited study. With the advent of next-generation sequencing technology, analysis of somatically-acquired mutations in patient samples has become a normal part of clinical practice in MDS patients. Interestingly, the most common class of mutations found in MDS patients are mutations in various components of the spliceosome. We have determined that these MDS- associated spliceosome gene mutations lead to alterations in innate immune signaling pathways and compromise the function of myeloid cells in mouse models of spliceosome-mutated MDS. This leads to a significant defect in host defense. Based on these preliminary studies, we have hypothesized that MDS patients with spliceosome mutations are at an increased risk of infection because of immune dysfunction in their myeloid cells. To test this hypothesis, we will investigate the effects of spliceosome mutations on host defense using: (1) ex vivo studies with mouse and human neutrophils, (2) ex vivo studies with mouse and human macrophages, and (3) in vivo studies in mice expressing mutant spliceosome genes and in an analysis of clinical data from patients with MDS. These studies will determine the mechanisms underlying host defense defects in MDS patients with spliceosome mutations and will provide important clinical data about patient risk stratification.

摘要 骨髓增生异常综合征（MDS）是一种造血干细胞疾病，其特征在于骨髓细胞增生异常。 分化缺陷和发育不良的血细胞产生。大多数MDS患者死于疾病相关的 原因，感染或感染性并发症是最常见的原因。虽然已知骨髓 细胞在MDS患者中表现出功能缺陷，这些缺陷的程度和原因尚不清楚， 对宿主防御的相应影响的研究有限。随着新一代 随着测序技术的发展，分析患者样本中的体细胞获得性突变已成为一种常态。 MDS患者临床实践的一部分。有趣的是，在MDS中发现的最常见的突变类型 患者是剪接体的各种组分中的突变。我们已经确定这些MDS- 相关的剪接体基因突变导致先天免疫信号传导途径的改变， 在剪接体突变的MDS小鼠模型中损害骨髓细胞的功能。这导致 宿主防御的重大缺陷。基于这些初步研究，我们假设MDS 剪接体突变的患者感染的风险增加，因为免疫功能障碍， 他们的骨髓细胞为了验证这一假设，我们将研究剪接体突变对宿主的影响， 使用：（1）小鼠和人中性粒细胞的离体研究，（2）小鼠和人中性粒细胞的离体研究， 人巨噬细胞，和（3）在表达突变剪接体基因的小鼠中的体内研究和在分析中 MDS患者的临床数据。这些研究将确定宿主防御的潜在机制 剪接体突变的MDS患者中的缺陷，并将提供有关患者风险的重要临床数据 分层