Penn State investigator receives $7.3 million grant for research on cellular protein

A faculty member in Penn State's College of Agricultural Sciences has received a $7.3 million grant for innovative research on a cellular protein that could be a target for enhancing immune function in response to a variety of diseases and environmental toxins.

Gary Perdew, John T. and Paige S. Smith Professor in Agricultural Sciences, received the award from the National Institute of Environmental Health Sciences, part of the National Institutes of Health. The funding will support an eight-year research initiative titled, "Activation of the Ah receptor and epithelial integrity."

The grant is part of NIEHS' Revolutionizing Innovative, Visionary Environmental-health Research, or RIVER, program. According to the institute's website, a RIVER grant is designed to support the research program of outstanding investigators in the environmental health sciences. The program gives scientists intellectual and administrative freedom, as well as sustained support to pursue research in novel directions and to embark on long-term projects that have unusual potential to achieve greater impacts.

Perdew, a toxicologist who also serves as interim head of the Department of Veterinary and Biomedical Sciences, has spent more than three decades studying the Ah (aryl hydrocarbon) receptor. This protein has been shown to play an important role in maintaining the integrity of epithelium -- layers of cells that line barrier tissues such as skin, lungs and the gastro-intestinal tract -- and regulating the immune status in these tissues.

"The Ah receptor is activated by ligands, which are specific chemicals produced by combustion of organic matter and which include dioxin and polycyclic aromatic hydrocarbons that are found in tobacco smoke," Perdew said. "This receptor also binds some endogenous ligands, such as tryptophan metabolites and certain microbial metabolites in the gut or in infection sites."

He explained that when the receptor binds with these ligands, it triggers a physiological response.

"Data show that this can enhance the inflammatory response and help protect you from infection," he said. "But too much stimulation can cause toxicity and perhaps contribute to chronic disease. Some activation is good, but at what point it becomes detrimental is not known."

Perdew noted that when it comes to dietary or bacterial production of ligands, some people's gut flora may cause more stimulation of the Ah receptor, and that could predispose them to some diseases, such as colon cancer.

"We are going to look at bacteria in different people's gut and ask, 'Do we vary in our ability to make Ah receptor ligands from various dietary compounds?"

The grant also will support studies examining how activating the Ah receptor in the epithelial layer of the skin or gut affects barrier function, production of antimicrobial peptides and resistance to invading bacteria.

"In addition, we're interested in targeting the Ah receptor for therapeutic purposes," he said. "For example, if you have dermatitis, which is disruption of the skin barrier, would activating this receptor enhance skin barrier function?"

This body of work has important health implications related to diet, chronic diseases and exposure to environmental toxins, according to Perdew. And this grant will give his laboratory the flexibility to pursue long-term, higher-risk studies that might not be possible with a shorter-term project aimed at addressing just one specific research question.

"Human populations increasingly are at risk for developing chronic diseases, and a major contributing factor is epithelial barrier dysfunction," Perdew said. "So there's a need to better understand the activities of this enigmatic receptor, the influence of different classes of ligands, and the appropriate level of Ah receptor activation needed to maintain health."