MIF-mediated Mechanisms in Emphysema

MIF 介导的肺气肿机制

基本信息

批准号：
10083682
负责人：
PATTY J LEE
金额：
--
依托单位：
DURHAM VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083682
关键词：
Address Affect Age Age-Months Agonist BRCA1 Protein BRCA1 gene Biological Biological Aging Cause of Death Cell Death Cell Survival Cells Chronic Chronic Obstructive Airway Disease Cigarette smoke-induced emphysema Cyclin-Dependent Kinase Inhibitor 2A DNA Damage DNA Repair DNA Repair Gene Data Disease Elderly Endothelial Cells Endothelium Epidemic Experimental Models Functional disorder Gases Gene Expression Genetic Human Immune Incidence Injury Knock-in Mouse Knockout Mice Lead Link Luciferases Lung Lung diseases Mediating Migration Inhibitory Factor Molecular Morbidity - disease rate Mus Obstruction Organ Oxidants Pathogenesis Pathway interactions Plasma Predisposition Prevention Proteins Proto-Oncogene Proteins c-akt Publishing Pulmonary Emphysema Reporting Risk Factors Role Signal Transduction Smoker Source Therapeutic Therapeutic Effect airway obstruction base cigarette smoke cigarette smoke-induced cigarette smoke-induced COPD clinically relevant cohort cytokine effective therapy efficacy testing exposure to cigarette smoke functional loss human disease in vivo in vivo Model insight interest novel novel therapeutic intervention novel therapeutics oxidant stress oxidative DNA damage prevent primary endpoint protein activation protein expression receptor reconstitution response senescence small molecule therapeutic evaluation therapeutic target tool

项目摘要

Chronic Obstructive Pulmonary Disease (COPD) has reached epidemic proportions but specific therapies do not exist. Emphysema is a major subset of COPD and is defined histopathologically as enlarged airspaces, which result in ineffective gas exchange. Aside from age, cigarette smoke (CS) exposure is one of the most common identifiable risk factors for COPD. Understanding mechanisms of CS-induced emphysema will allow us to develop effective therapies for a potentially modifiable lung disease that affects millions. Our proposal addresses the gaps in the field by identifying that inadequate levels of a novel cytokine, Macrophage migration inhibitory factor (MIF), or a loss of its signaling via the CD74 receptor, leads to emphysema. In addition, we will provide in vivo proof-of-concept studies that MIF-CD74 augmentation, using recently discovered small molecule agonists, will be therapeutic against emphysema. The molecular basis for emphysema in MIF- KO, CD74-KO mice and in human COPD may be the loss of cell survival protein activation (AKT), decreased DNA repair protein expression (BRCA1) and the simultaneous induction of senescence molecule p16 – especially in the lung endothelium. We will use clinically relevant experimental models of CS exposure, as well as novel lung- and endothelial-targeted genetic tools to identify underlying mechanisms mediating MIF-CD74 and p16 effects in the lung. Our studies reveal a unifying paradigm in which CS-induced deficiencies in MIF-CD74 leads to the induction of deleterious molecules, which predispose to emphysema. Restoring MIF-CD74 be a new therapeutic approach for emphysema. Our overall hypothesis is that endothelial MIF-CD74 signaling is critical in protecting against emphysema through its activation of key cell survival and DNA repair molecules and the suppression of senescence protein p16. We will complete the following aims in order to prove our hypothesis. Aim 1. Identify the role of endothelial MIF in CS-induced emphysema and whether MIF augmentation in vivo has therapeutic effects against emphysema; Aim 2. Determine the contributions of AKT and BRCA1 to MIF-CD74-mediated cell survival, DNA repair and p16 suppression in endothelial cells. Aim 3: Determine whether preventing p16 induction in vivo has therapeutic effects in MIF-KO and CS-induced emphysema. Our studies will expand our basic understanding of the molecular and cellular aspects of emphysema and inform new therapeutic approaches using MIF augmentation and/or p16 targeting.

慢性阻塞性肺疾病（COPD）已达到流行比例，但特定的疗法没有存在。肺气肿是COPD的主要子集，在组织病理学上被定义为扩大空间，该空域是导致无效的气体交换。除了年龄，香烟烟（CS）暴露是最常见的 COPD可识别的风险因素。了解CS诱导的肺气肿的机制将使我们能够为影响数百万的潜在可修改的肺部疾病开发有效的疗法。我们的提议解决通过确定新型细胞因子的水平不足，巨噬细胞迁移抑制作用，该领域的差距不足因子（MIF），或通过CD74受体失去信号传导，导致肺气肿。此外，我们将提供体内概念验证研究，MIF-CD74增强，使用最近发现的小分子激动剂，将是针对肺气肿的治疗方法。 MIFKO，CD74-KO小鼠和中肺气肿的分子基础人COPD可能是细胞存活蛋白激活（AKT）的丧失，改善了DNA修复蛋白表达（BRCA1）和感应分子p16的简单诱导 - 尤其是在肺海植物中。我们将使用CS暴露的临床相关实验模型，以及新型的肺和内皮靶向识别介导MIF-CD74和p16效应的基本机制的遗传工具。我们的研究揭示了一个统一的范式，其中CS诱导的MIF-CD74缺陷导致有害的诱导分子，易感性。恢复MIF-CD74是一种新的治疗方法气肿。我们的总体假设是内皮MIF-CD74信号对于保护至关重要肺气肿通过其激活钥匙细胞存活和DNA修复分子的激活以及抑制感应蛋白p16。我们将完成以下目标，以证明我们的假设。目标1。识别内皮MIF在CS诱导的肺气肿中的作用以及MIF在体内是否已使用治疗对肺气肿的影响； AIM 2。确定AKT和BRCA1对MIF-CD74介导的细胞的贡献内皮细胞中的存活，DNA修复和p16抑制。目标3：确定是否防止P16 体内诱导在MIF-KO和CS诱导的肺气肿中具有治疗作用。我们的研究将扩大我们的对肺气肿的分子和细胞方面的基本理解，并为新疗法提供信息使用MIF增强和/或P16靶向方法。