Hülya Bayır, MD Receives Grant to Mitigate Radiation Treatment Toxicity

Professor Hülya Bayır, MD received a U01 award from the National Institute of Allergy and Infectious Diseases entitled “Radiation Mitigators Targeting Regulated Necrosis Pathways of Parthanatos Pyroptosis.” The project will explore the potential of small molecule compounds to mitigate radiation toxicity that may have been triggered by an irradiation event such as radiotherapy, occupational activities, terrorism or nuclear accidents.

“Today’s physicians need new medical products to mitigate as well as to treat the consequences of radiation exposure,” said Hülya Bayır, MD, who is director of the Children's Neuroscience Institute, academic chief and director of research and professor of Critical Care Medicine, Environmental and Occupational Health, and Pediatrics at the University of Pittsburgh. “Our research has shown that the therapeutic window of opportunity for products to inhibit necrotic death pathways will likely be 24 hours after irradiation.”

The known cellular response to irradiation begins with radiolysis of water to produce an immediate burst of free radicals, which is followed by a dose-dependent and continuous mitochondrial overproduction of reactive oxygen species. Within the initial 1-2 days after exposure, the direct effects of ionizing radiation and water radiolysis products are realized primarily via apoptotic cell death pathways in rapidly proliferating hematopoietic cells and gastrointestinal epithelial cells.

Dr. Bayır’s team and others have shown that necrotic cell death ensues via direct and indirect pathways from increased generation of pro-inflammatory cytokines, chemotactic factors and lipid mediators as well as from translocation of bacteria from the intestine to blood stream later in the course of the radiation disease.

“Mitochondria are at the crux of multiple regulated cell death programs and inflammatory response to host or pathogen derived antigen,” Dr. Bayır explained. “The goal of our project is to decipher mitochondrial PARP1 and NLRP3 driven signaling pathways associated with parthanatos and pyroptosis in mechanism-based discovery of radiomitigators.”

Project collaborators at the University of Pittsburgh include Robert Clark, MD from the Department of Critical Care Medicine, Michael Epperly, PhD from the Department of Radiation Oncology, Peter Wipf, PhD from the Department of Chemistry, Yulia Tyurina, PhD from the Department of Environmental and Occupational Health and Indira Shrivastava, PhD from the Department of Computational and Systems Biology.