Grant: Discovery Grants Program - Individual

Intermediate filaments (IFs) are with microtubules and actin microfilaments the major cytoskeletal components of most mammalian cells. Modifications in K8/18 IFs organisation and formation of keratin containing aggregates called Mallory bodies (MBs) are common to many human chronic liver diseases such as alcoholic hepatitis, Wilson's disease, Indian childhood cirrhosis and liver steatosis in obesity. Recent studies realised by us and others have shown evidences that K8/18 play an important role in the protection of hepatocytes against chronic stress-induced liver injuries. The long-term objective of our project is to determine the molecular mechanism by which K8/18 accomplish their protective role in hepatocytes. More specifically we want to 1) study the role of keratin phosphorylation on specific sites (K8 S73, K8S431 and K18 S52) in the apoptotic signalling pathway in hepatocytes. In this regard we will test the hypothesis that keratins act as a key regulator in maintaining the delicate balance between pro and anti-apoptotic signals molecules by directly interacting with pro (FASr) and anti (pAKT) apoptotic molecules. 2) There is accumulating evidence that sites and pattern- specific phosphorylation of keratin play a key role in the protection of hepatocytes against stress. Thus, we want to characterize K8/18 phosphorylation paterns in control and GF treated hepatocytes and perform functional analysis of K8/18 phosphorylation. The characterization of the modifications that affect keratins (post-translational modification, association with other proteins) during the response of hepatocytes to stress and the study of their relation with hepatocytes functions will constitutes an important step in our understanding of the molecular mechanisms used by keratins to accomplish their functions. This will directly lead us to further research on the cross-talk between keratins and cell signalling, and on how keratins affect disease pathogenesis.