Role of Mkp-1 in pneumonia

Wancket, Lyn

Abstract

The Candidate: Dr. Lyn M. Wancket, a licensed veterinarian, is currently enrolled in a veterinary pathology and graduate training program in the Department of Veterinary Biosciences at The Ohio State University (OSU), This K01 SERCA will support five years of her career, including two years of her doctoral research and three years of her junior faculty career. The Environment: Dr. Wancket's sponsor, Dr. Yusen Liu, Ph.D., is an Associate Professor in the Department of Pediatrics (OSU) and Principal Investigator at the Research Institute at Nationwide Children's (TRINCH). Dr. Liu has expertise in biochemistry and innate immunity and has extensive experience mentoring post doctoral and medical fellows, including K award trainees. The Training Plan: This five year career development plan is divided into two phases. Years one and two of the K award will allow Dr. Wancket to devote her full time to research training that will culminate in her Ph.D. Years three through five will promote Dr. Wancket's transition to an independent researcher with a faculty appointment in the Department of Veterinary Biosciences. The Proposal: MAPK phosphatase (Mkp)-1 is a key suppressor of mitogen-activated protein kinase (MAPK) activity. Mkp-1 preferentially dephosphorylates p38 and JNK MAPKs, suppressing cytokine production in response to bacterial ligands. While relatively little is known Mkp-1 interactions in pulmonary infections, Mkp-1- /- mice have enhanced cytokine release and morbidity during systemic challenge with E. coli, Staphylococcus aureus, and bacterial endotoxin. The central hypothesis is that Mkp-1 negatively regulates the innate immune response and limits clinical disease during primary and secondary bacterial pneumonia. In this mentored research award, this hypothesis will be tested using mouse models of Streptococcus pneumoniae and influenza infection, as well as S. pneumoniae challenged primary cells.

Public Health Relevance

(provided by applicant): Secondary bacterial pneumonia is a major cause of hospitalization and death during seasonal and pandemic influenza outbreaks, and this disease syndrome of often characterized by excessive pro-inflammatory cytokine production. Although there are clearly interactions between influenza virus and bacteria such as S. pneumoniae, the underlying mechanisms are incompletely understood, hindering the development of targeted therapies for critically ill patients. The overall research goal of this proposal is to understand the role of the endogenous immune suppressor Mkp-1 in both primary and secondary bacterial pneumonia, including implications for treatment.