Role of MIF and CD74 in the pathogenesis of emphysema

MIF和CD74在肺气肿发病机制中的作用

• 批准号: 10543511
• 负责人: Maor Sauler
• 金额: $ 68.48万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543511
• 关键词: Address; Agonist; Alleles; Apoptosis; Attenuated; Biology; Cause of Death; Cell Aging; Cells; Chronic; Chronic Obstructive Pulmonary Disease; Cigarette smoke-induced emphysema; Cytoprotection; DNA Damage; Data; Development; Disease; Disease Progression; Endothelial Cells; Endothelium; Flow Cytometry; Genetic; Genetic Polymorphism; Genetic study; Goals; Histology; Homeostasis; Human; Image; Immune; LoxP-flanked allele; Lung; Lung diseases; MAPK3 gene; Macrophage; Mediating; Methods; Migration Inhibitory Factor; Molecular; Mouse Strains; Mus; Oxidative Stress; Oxidative Stress Induction; Pathogenesis; Pathologic; Pathway interactions; Patients; Predisposition; Proteins; Pulmonary Emphysema; Reporter; Research Personnel; Risk Factors; Role; Severities; Severity of illness; Signal Pathway; Signal Transduction; Slice; Smoker; Study models; Testing; Therapeutic; Tissues; Translating; Treatment Efficacy; United States; Visualization; Work; X-Ray Computed Tomography; cell type; cigarette smoke; cigarette smoke-induced; cytokine; effective therapy; exposure to cigarette smoke; gain of function; improved; loss of function; migration; modifiable risk; mouse model; new therapeutic target; novel; oxidative DNA damage; pharmacologic; promoter; protective effect; receptor; resilience; response; senescence; small molecule; stress reduction

PROJECT SUMMARY Emphysema is a common pathologic manifestation of Chronic Obstructive Pulmonary Disease (COPD), the fourth leading cause of death in the United States. The most important modifiable risk factor for emphysema is chronic exposure to cigarette smoke (CS). Yet, not all smokers develop emphysema and, therefore, cellular responses to CS are important mechanisms underlying disease progression. Our long-term goal is to define the cellular responses to CS and oxidative stress that protect the lung from emphysema. We have identified a cytoprotective role for the innate immune cytokine Macrophage Migration Inhibitory (MIF). MIF decreases oxidative stress and consequences of oxidative stress (e.g. cellular senescence and apoptosis) in lung endothelial cells, and mice with a genetic deletion of Mif are susceptible to emphysema. MIF is secreted in response to CS, but, paradoxically, MIF is decreased in patients with severe COPD. Targeting MIF, or its downstream pathways, may be therapeutic. However, MIF is a pleiotropic molecule with broad regulatory effects. To translate MIF biology into therapy, it will be essential to dissect out its cytoprotective pathways. Our goal for this proposal is to determine the mechanisms through which MIF antagonizes the development of emphysema. Our preliminary data suggests MIF mediates its protective effects through its receptor CD74. Our hypothesis is MIF protects against the development of emphysema by mitigating CS-mediated endothelial senescence in a CD74 dependent manner. In Aim 1, we will define the mechanism through which the MIF-CD74 interaction reduces endothelial senescence. In Aim 2, we will determine the role of endothelial CD74 in regulating susceptibility to emphysema. In Aim 3, we will determine the therapeutic potential of targeting MIF-CD74 interactions in emphysema. Completion of these aims will significantly advance our understanding of the pathogenesis of emphysema and may identify precision-based approaches based on MIF biology for treating patients with emphysema.

项目摘要 肺气肿是慢性阻塞性肺疾病（COPD）的常见病理表现， 美国第四大死亡原因。肺气肿最重要的可修改风险因素是 长期暴露于香烟烟雾（CS）。但是，并非所有吸烟者都会发展出肺气肿，因此，细胞 对CS的反应是疾病进展的重要机制。我们的长期目标是定义 细胞对CS的反应和保护肺部免受肺气肿的氧化应激。我们已经确定了 先天免疫细胞因子巨噬细胞迁移抑制（MIF）的细胞保护作用。 MIF减少 氧化应激的氧化应激和后果（例如，肺细胞衰老和凋亡） 内皮细胞和具有MIF遗传缺失的小鼠容易受到肺气肿的影响。米夫被分泌 对CS的反应，但矛盾的是，严重COPD患者的MIF减少。针对MIF或ITS 下游途径可能是治疗性的。但是，MIF是一种具有广泛调节作用的多效分子。 为了将MIF生物学转化为治疗，必须剖析其细胞保护途径。我们的目标 该建议是确定MIF拮抗肺气肿发展的机制。 我们的初步数据表明，MIF通过其受体CD74介导了其保护作用。我们的假设是 MIF通过缓解CS介导的内皮衰老A在A中预防肺气肿的发展 CD74依赖方式。在AIM 1中，我们将定义MIF-CD74相互作用的机制 减少内皮衰老。在AIM 2中，我们将确定内皮CD74在调节中的作用 对肺气肿的敏感性。在AIM 3中，我们将确定针对MIF-CD74的治疗潜力 肺气肿的相互作用。这些目标的完成将大大提高我们对 肺气肿的发病机理，并可能基于MIF生物学来识别基于精确的方法用于治疗 肺气肿的患者。