MIF Genetics & Therapeutics in Emphysema

About This Grant

Background and Innovation: 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 emphysema/COPD. Our proposal addresses the current lack of effective preventatives and therapeutics in emphysema/COPD in the following ways: 1. We found that low levels of immune proteins, called Macrophage migration inhibitory factor (MIF), lead to age- or CS-related emphysema, 2. We found low MIF increases susceptibility to one of the most lethal complications of COPD—bacterial pneumonia, 3. We identified the gene-patterns, called polymorphisms, in the region of the MIF gene that controls its protein levels and now have humanized MIF mice that can be challenged with CS and bacterial infection, 4. We linked human MIF polymorphisms to susceptibility to COPD and a common bacterial infection called S. Pneumoniae and now have humanized MIF mice to perform proof-of-concept studies and 5. We developed and tested ways to restore MIF levels in the entire body and specifically in the lungs. Our main objective of this competitive renewal proposal is to define the biologic relationships between MIF genetic polymorphisms, emphysema/COPD and its lethal complication, S. pneumoniae infection, and to test the therapeutic impact of MIF augmentation in CS-induced emphysema/COPD and S. pneumoniae infection. We will use innovative, genetic mouse models and translate our findings to unique human ex vivo lung systems, which will also allow us to perform pre-clinical pharmacologic testing of our new MIF augmenters / agonists. We will identify MIF and MIF-related gene signatures that correlate with the presence/absence of a COPD/emphysema diagnosis. Significance and Impact to Veterans Healthcare: Upon completion of these studies, we will expand our basic understanding of MIF genetics in CS-induced chronic lung disease and bacterial pneumonia, thereby providing potential novel lung-targeted, personalized therapeutics. These advancements are particularly significant for Veterans' healthcare, where COPD is notably prevalent and associated with high mortality rates. COPD is a leading cause of morbidity among veterans, exacerbated by their unique risk factors, including higher rates of smoking and exposure to environmental pollutants during service. The development of personalized therapeutics, informed by both genetic and therapeutic studies, may revolutionize diagnostic and treatment paradigms for veterans. This approach aligns with the growing demand for precision medicine in Veterans' healthcare, offering a pathway to more effective, individualized care strategies that can address the complex healthcare needs of our veterans who suffer from chronic obstructive lung diseases. Path to translation/implementation: 1. Proof-of-Concept Validation: Utilizing our humanized MIF mouse models, we will first confirm the therapeutic potential of modulating MIF levels in treating CS-induced emphysema/COPD and bacterial pneumonia. These models, which mirror human MIF genetic polymorphisms, provide a robust platform for validating our hypotheses under controlled experimental conditions. 2. Pre-Clinical Testing in ex vivo Human Lung Models: By leveraging both human and mouse PCLS as well as state-of-the-art Spatial Transcriptomic technology, we will be able to translate the therapeutic potential of MIF augmentation while revealing new gene-gene and cell-cell interactions in lungs.