Objective This is a proposal to define a fundamentally new and potentially dominant pathway of airway inflammation involving the p53 homolog p73 acting through regulators of cytokine mRNA stability. We anticipate that the studies described herein will contribute to our understanding of acute and chronic airway diseases and the development of novel therapies to combat them. The proposal is divided into four parts: 1. Establish a Role for p73 in the Innate Immune Response in the Upper Airways Our genetic models for loss of p73 function reveal the unexpected finding that ciliated airway epithelia play a major and perhaps dominant role in airway inflammation. We will exploit genetic and cellular models to establish the broader significance of these cells and of p73 in regulating the innate immune response and how they contribute to human disease. 2. Define the Signaling Pathways of the Innate Immune Response in Airway Epithelia We will use mass spectrometry, shRNA technology, and small molecule inhibitors to dissect these pathways linking p73 to airway inflammation and develop chemical screens as a basis of therapeutic intervention. 3. Determine the Genetic Targets of p73 that Control Airway Inflammation Our preliminary work has identified key regulators of mRNA stability downstream of p73, and has implicated them in the destabilization of inflammatory ytokine mRNAs. These observations suggest a novel mechanism for the control of airway inflammation involving mRNA stability. 4. Mouse Models for Dcp1² Loss-of-Function The identification of Dcp1² as the strongest target of p73 offers a new and fundamental approach to the control of airway inflammation. Genetic models in mice will provide new insights into the role of mRNA stability for airway inflammation and novel models of human airway disease. Fields of science medical and health sciencesbasic medicineimmunologynatural scienceschemical sciencesanalytical chemistrymass spectrometry Keywords Toll-like receptors airway inflammation cytokines mRNA decapping p73 Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-AG-LS6 - ERC Advanced Grant - Immunity and infection Call for proposal ERC-2008-AdG See other projects for this call Funding Scheme ERC-AG - ERC Advanced Grant Coordinator CENTRE INTERNATIONAL DE RECHERCHE AUX FRONTIERES DE LA CHIMIE FONDATION Address Allee g monge 8 67000 Strasbourg France See on map Region Grand Est Alsace Bas-Rhin Activity type Research Organisations Principal investigator Frank Daniel Mckeon (Prof.) Administrative Contact Jean Gagneux (Mr.) Links Contact the organisation Opens in new window Website Opens in new window EU contribution € 2 470 400,00 Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all CENTRE INTERNATIONAL DE RECHERCHE AUX FRONTIERES DE LA CHIMIE FONDATION France EU contribution € 2 470 400,00 Address Allee g monge 8 67000 Strasbourg See on map Region Grand Est Alsace Bas-Rhin Activity type Research Organisations Principal investigator Frank Daniel Mckeon (Prof.) Administrative Contact Jean Gagneux (Mr.) Links Contact the organisation Opens in new window Website Opens in new window
