Yale Researcher Using NIH Grant to Study Emphysema Mechanisms
The National Institutes of Health (NIH) has awarded a five-year grant to a Yale researcher to support his work on the molecular and cellular mechanisms underlying emphysema, a severe form of chronic obstructive pulmonary disease (COPD).
The R01 grant, titled “Role of MIF and CD74 in the pathogenesis of emphysema,” was awarded to Maor Sauler, MD, an assistant professor of medicine at Yale School of Medicine, in Connecticut.
“Successful completion of [this study] may uncover novel therapeutic targets to treat emphysema,” according to Sauler’s grant abstract.
Emphysema is a severe form of COPD characterized by gradual lung tissue damage and the destruction of alveoli — the tiny air sacs within the lungs that play a key role in gas exchange.
Sauler’s research involves looking at the way in which the body’s cellular response is affected by cigarette smoke, a major risk factor for emphysema, and aiming to unearth the mechanisms underlying disease progression.
“COPD is a disease that commonly occurs in elderly individuals and following years of cigarette smoke exposure, but not all smokers develop COPD,” Sauler said in a university press release.
Since not all smokers develop emphysema despite it being a major risk factor, one of the project’s long-term goals is to investigate the mechanisms that may have a protective effect against the lung disorder.
“Our lab identified a cellular stress response protein called macrophage migration inhibitory factor (MIF) that is impaired in susceptible individuals,” Sauler said. “Over the next five years, we are hoping to understand how impaired MIF responses increase susceptibility to lung injury and emphysema, and translate that understanding into novel therapies for COPD.”
Normally, MIF is a pro-inflammatory signaling molecule involved in the body’s response to bacteria. However, in lung endothelial cells — those lining blood vessels in the lungs — MIF seems to reduce oxidative stress caused by cigarette smoke, as well as many of its consequences, including cell death and senescence (aging). Of note, oxidative stress is a type of cellular damage caused by high levels of oxidant molecules.
Additionally, mice genetically modified to lack MIF have been found to be more susceptible to emphysema.
Although MIF is released in response to cigarette smoke, it also is decreased in patients with severe emphysema. Therefore, targeting MIF may potentially be the key to future COPD therapies, according to the researcher.
Yet, MIF is a wide-reaching molecule within the body that has several potential cellular downstream effects. The first step to develop new therapies targeting MIF will be to dissect its various protective effects, including its interactions with its receptor, CD74, which may be crucial for its ability to counter the development of emphysema.
Sauler and his group believe that MIF helps protect against emphysema by preventing cigarette smoke-mediated endothelial cell senescence in a way that is dependent on the interaction between MIF and CD74. They are now planning to use the R01 grant to further investigate this potential connection.
Naftali Kaminski, MD, who serves as Sauler’s section chief at Yale, said he’s been “excited” to see the investigator “develop into [an] independent and influential” researcher. Kaminski noted that another Yale researcher, Jose Gomez-Villalobos, MD, received a five-year NIH grant last year.
He said the two researchers are “critical to us as we address our mission, which is to help patients with lung disease.”