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Researchers at the University of South Alabama College of Medicine recently were awarded a $1 million four-year grant from the National Institutes of Health (NIH) to study molecular mechanisms that contribute to acute lung injury resulting from bacterial infections and to explore a novel approach for treatment.
The NIH-funded research focuses on the bacterium pseudomonas aeruginosa (PA), a common cause of hospital-acquired lung infections that can progress to a severe loss of lung function – termed acute lung injury – and ultimately death.
Studying lung endothelial cells – the cells that line the blood vessels of the lung – the researchers noted that exposure to PA induced a dramatic up-regulation in the activity of cAMP-phosphodiesterases, a group of enzymes that degrade the signaling molecule cAMP.
“With this grant, we will test the hypothesis that the bacteria-induced activation of CAMP-phosphodiesterase activity depresses endothelial cAMP signaling, which in turn weakens endothelial barrier integrity, leading to formation of edema and exacerbation of lung injury,” said Wito Richter, Ph.D., assistant professor of biochemistry and molecular biology at the USA College of Medicine and principal investigator on the grant.
To tackle this project, he joins forces with several investigators at USA and the University of Alabama at Birmingham, each contributing their unique knowledge and skill sets towards the experimental plan. This team of scientists includes molecular biologist Dr. Mikhail Alexeyev, microbiologist Dr. Jonathan Audia and physiologist Dr. Diego Alvarex from the USA College of Medicine as well as Dr. Jean-Francois Pittet, a critical care physician at the University of Alabama at Birmingham.
“Combining the expertise of the different co-investigators will be the key to success and hopefully will achieve results that exceed what each researcher could have accomplished independently,” Richter said.
The research conducted by this grant holds promising potential to impact patient care, as there is an urgent need for new therapeutic approaches — particularly strategies that bridge the current disconnect between bench and bedside.
“Patient mortality and morbidity remain high because there are few effective treatments for acute lung injury,” Richter said. “Although the disease is well recognized and several promising therapeutic targets were identified in preclinical studies, these strategies generally disappointed when translated to the clinical setting. As inhibitors of cAMP phosphodiesterases, the enzymes studied under this grant, are already FDA-approved for other indications such as chronic obstructive pulmonary disease, these drugs could be re-purposed for treating acute lung injury.”
The Research Project Grant, or R01 grant, is the original and historically oldest funding mechanism used by the NIH. The R01 provides support for health-related research and development based on the mission of the NIH.
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