Grant: Discovery Grants Program - Individual

A long-standing focus of my research has been the development of a mathematical framework representing the biochemical and biomechanical properties of the dynamics of intermediate filaments (IF), an essential component of cytoskeletal networks of eukaryotic cells. IF proteins transition from a soluble form into complex insoluble filamentous fibre networks providing mechanical strength to cells. Network dynamics regulates fundamental cellular functions such as cell movement, signal transduction and mechanotransduction. IF organization and dynamics relies on the interplay between assembly, disassembly and intracellular transport regulated by post-translational modifications. These processes play a role at different timescales and their interplay results in IF structures that locally re-organize despite the maintenance of a global steady state configuration within the cell. Defects in IF dynamics impair their cellular function. The first objective of my proposal is to study a major contributor to IF dynamics, namely IF transport in cells. Several competing processes such as antagonistic motor protein driven transport and actin retrograde flow move IF in cells. I intend to investigate the mechanisms regulating motility of IF in cells. Mutations in IF protein genes are linked to defects in the organisation of IF in networks and appearance of cytoplasmic IF proteins aggregates, often coinciding with deregulation of turnover or motility of IF proteins. The function, structure and dynamics of aggregates is still not understood. The second objective of my proposal is to identify disorders in IF dynamics leading to IF aggregation phenomena. To tackle key gaps in knowledge related to the function and structure of IF requires a combination of mathematics, biophysics and biology. To attack the two objectives of my proposal, my group will develop mathematical and computational models and theoretical tools to quantify the short- and long-term responses of models to perturbations. Model design will be guided by experimental data and iterative discussions with my experimentalist collaborators at Institut Pasteur (France), MOCA (Germany), DKFZ (Germany) and U Wisconsin (USA). Integrating experimental tractability from the conception of models will increase their descriptive and predictive power. Data will be used to calibrate models and cross-validate predictions. This approach will allow the identification of mechanisms regulating the IF motility in cells and perturbations in the IF dynamics causing aggregation. Understanding the dynamics of IF is essential to decipher IF organisation in cells. Importantly, my research program and its implementation in an international collaboration network will provide a unique and exemplary multidisciplinary environment for the training of a new generation of scientists able to handle mathematical tools and biological experimentations.