Paraoxonase-2 S311C Polymorphism Alters Glycosylation and Lactonase Activity

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DESCRIPTION (provided by applicant): This application is to provide support for a supervised research career development experience for Dr. David Stoltz in the field of airway cell biology. Dr. Stoltz has completed a combined M.D./Ph.D. program and is currently in the Pulmonary/Critical Care fellowship at the University of Iowa. His training plans include further didactic studies and laboratory training in cell and molecular biology and human genetics. These experiences will foster the development of Dr. Stoltz into an independent researcher and outstanding physician-scientist. Drs. Joseph Zabner, as primary mentor, and Michael Welsh, as co-mentor, will be responsible for ensuring the success of the career development plan. An advisory committee composed of experts in fields related to the proposed project will provide ongoing critical review and scientific as well as professional guidance. The proposed research will focus on regulation of Pseudomonas aeruginosa quorum sensing, an important determinant of bacterial virulence and biofilm formation, by paraoxonase-2 (PON2) in airway epithelial cells. We have recently shown that PON2 inactivates the P. aeruginosa quorum-sensing molecule, 3OC12-HSL and, of clinical interest, a common polymorphism in PON2 (Ser311Cys) impairs this response. My preliminary data suggest that differential glycosylation occurs between the PON2 variants. I hypothesize that the PON2 Ser311 Cys polymorphism results in impaired lactonase activity due to altered glycosylation and/or a PON2 trafficking/localization defect. The Specific Aims designed to test this hypothesis include: 1) Investigating which PON2 glycosylation sites undergo core glycosylation and modification, 2) Evaluating if the altered glycosylation pattern in the PON2 variants represents altered PON2 trafficking/localization, and 3) Determining if glycosylation is important for PON2 lactonase activity. Both the mentors and the University of Iowa are highly committed to Dr. Stoltz's academic success and development into an independent researcher. As a sign of this commitment, he will join the faculty of the Division of Pulmonary/Critical Care in July 2007. Dr Stoltz's research plan has great relevance to public health as P. aeruginosa is a common cause of infection and death in hospital acquired infections and cystic fibrosis, the most common inherited, lethal disorder in the United States. Findings from the proposed project will hopefully uncover new therapeutic options for P. aeruginosa infections.