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.

Public Health Relevance

COPD is the only disease among the top 10 causes of death worldwide with a rising incidence and will soon reach epidemic proportions. Emphysema, or loss of functional airspaces, is a major feature of COPD but specific therapies do not exist. We identified a novel cytokine, Macrophage Migration Inhibitory Factor (MIF), and its receptor, CD74 as potential therapeutic targets. This proposal will allow us to define the mechanisms of action of MIF-CD74 and to test the efficacy of targeting MIF-CD74 in the prevention and treatment of emphysema.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX003265-05
Application #
9864017
Study Section
Respiration (PULM)
Project Start
2017-01-01
Project End
2021-09-30
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Durham VA Medical Center
Department
Type
DUNS #
043241082
City
Durham
State
NC
Country
United States
Zip Code
27705
Schwede, Matthew; Wilfong, Erin M; Zemans, Rachel L et al. (2018) Effects of bone marrow-derived mesenchymal stromal cells on gene expression in human alveolar type II cells exposed to TNF-?, IL-1?, and IFN-?. Physiol Rep 6:e13831
Belsky, Justin B; Rivers, Emanuel P; Filbin, Michael R et al. (2018) Thymosin beta 4 regulation of actin in sepsis. Expert Opin Biol Ther 18:193-197
Marshall, Jeffrey D; Bazan, Isabel; Zhang, Yi et al. (2018) Mitochondrial dysfunction and pulmonary hypertension: cause, effect, or both. Am J Physiol Lung Cell Mol Physiol 314:L782-L796
Wang, Chaoqun; de Mochel, Nabora S Reyes; Christenson, Stephanie A et al. (2018) Expansion of hedgehog disrupts mesenchymal identity and induces emphysema phenotype. J Clin Invest 128:4343-4358