# MIF-mediated Mechanisms in Emphysema

> **NIH VA I01** · DURHAM VA MEDICAL CENTER · 2020 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 9864017
- **Project number:** 5I01BX003265-05
- **Recipient organization:** DURHAM VA MEDICAL CENTER
- **Principal Investigator:** PATTY J LEE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864017

## Citation

> US National Institutes of Health, RePORTER application 9864017, MIF-mediated Mechanisms in Emphysema (5I01BX003265-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9864017. Licensed CC0.

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