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) 已达到流行病的程度，但特定疗法并未达到流行程度肺气肿是 COPD 的一个主要亚型，在组织病理学上定义为气腔扩大。除了年龄之外，香烟烟雾（CS）暴露也是导致气体交换无效的原因之一。了解慢性阻塞性肺病 (COPD) 诱发的肺气肿的机制将使我们能够我们的提案旨在针对影响数百万人的潜在可改变的肺部疾病开发有效的疗法。通过确定新型细胞因子巨噬细胞迁移抑制的水平不足来弥补该领域的空白因子 (MIF) 或其通过 CD74 受体的信号传导丧失，会导致肺气肿。体内概念验证研究表明，使用最近发现的小分子激动剂增强 MIF-CD74，将是治疗MIF-KO、CD74-KO小鼠和肺气肿的分子基础。人类COPD可能是细胞生存蛋白激活（AKT）丧失、DNA修复蛋白表达减少 (BRCA1) 和同时诱导衰老分子 p16——尤其是在肺内皮细胞中。将使用临床相关的 CS 暴露实验模型，以及新型肺和内皮靶向我们的研究旨在确定介导 MIF-CD74 和 p16 在肺部作用的潜在机制的遗传工具。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易患肺气肿的分子，恢复 MIF-CD74 是一种新的治疗方法。我们的总体假设是内皮 MIF-CD74 信号传导对于预防肺气肿至关重要。肺气肿通过激活关键细胞存活和 DNA 修复分子以及抑制为了证明我们的假设，我们将完成以下目标。内皮 MIF 在 CS 诱导的肺气肿中的作用以及体内 MIF 增强是否具有治疗作用目的 2. 确定 AKT 和 BRCA1 对 MIF-CD74 介导的细胞的贡献内皮细胞的存活、DNA 修复和 p16 抑制目标 3：确定是否阻止 p16。体内诱导对 MIF-KO 和 CS 诱导的肺气肿具有治疗作用，我们的研究将扩大我们的研究范围。对肺气肿分子和细胞方面的基本了解并为新疗法提供信息使用 MIF 增强和/或 p16 靶向的方法。