The Role of Intermediate Filaments in Inflammation

Abstract: Intermediate filaments are highly conserved eukaryotic cytoskeletal proteins present in nearly every cell in the body. Although initially thought to simply provide structural support to cells, intermediate filaments are now implicated in a variety of biological processes due to their numerous protein interactions. Due to the number of intermediate filament monomers, more than 70 in humans, and the complexity of their regulation, more than 100 posttranslational modification sites, gaps remain in our understanding of the molecular mechanisms by which they are regulated and by which they contribute to many biological processes. To begin to fill these gaps, we seek to define molecular mechanisms by which intermediate filaments are regulated in cells and to define how intermediate filaments contribute to inflammation by focusing on their role in neutrophil inflammatory processes and migration. This proposal builds on the PIs previous experience investigating intermediate filament function during bacterial infection by proposing to leverage new cellular models of immortalized neutrophil populations with established screening approaches successfully use by the PI to define molecular mechanisms by which the intermediate filament vimentin contributes to inflammatory processes. The flexibility in funding provided by this R35 program will enable the PI the flexibility to follow the most promising lines of investigation and to leverage the proposed approaches to train junior scientists within the laboratory. The successful completion of the proposed studies is highly likely to improve our general understanding about the biological processes in cells to which intermediate filaments contribute and to our understanding of the mechanisms by which neutrophil function is regulated during inflammation.