Innate Immunity: Influence of the Extracellular Matrix Component Versican in Response to Lung Infections

• Applicant: Dr. Gernot Kaber
• Subject Area: Pneumology, Thoracic Surgery
• Term: from 2011 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 200105746

Lung infections place a higher burden on public health than other major diseases such as HIV, cancer, coronary heart disease, and stroke. The innate immune system, as the first line of defense against lung infection, includes pathogen recognition receptors, production of inflammatory mediators such as cytokines and chemokines, and leukocyte recruitment and activation. There is a paucity of information on the role of specific extracellular matrix (ECM) components in the innate immune response. It is planned to identify the composition and compartmentalization of the versican-enriched ECM that accumulates in the lungs of mice exposed to bacterial and viral infectious agents and to determine its role in leukocyte adhesion using in vivo and in vitro assays. Analyses will be carried out by microscopic and biochemical analyses as well as state of the art proteomics. The hypothesis that lung fibroblasts and epithelial cells in response to infectious agents produce a versican-enriched ECM will be validated in in vitro assays. Proteomics will be used to identify and quantify unknown proteins that are part of the versican-enriched complex. Furthermore, the requirement for versican in the innate immune response in lungs of infected mice will be determined by use of blocking antibodies to versican. In addition transgenic animals will be used that overexpress the versican V3 isoform in a tet-regulatable lung epithelial cell-specific manner. Thereby the role of V3 in pulmonary inflammation after challenge with infectious agents will be clarified. The central hypothesis of this proposal is that versican plays a key role in the innate immune response to lung infection by promoting the adhesion and activation of leukocytes. A better understanding of these specific ECM components that affect the inflammatory phenotype associated with lung diseases will assist in developing strategies to intervene with the key events responsible for the development and progression of lung disease.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Thomas N. Wight