EMBL-TL · The role of the p38 MAPK pathway in the liver: a genetic approach
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- —
- EU contribution
- €143,746
- Participants
- 1
- Scheme
- EIF
Lines connect the coordinator with its partners.
Project objective
Cytokine activated inflammatory signalling pathways have been implicated as important mediators of liver injury and are thought to be involved in the development of hepatocellular carcinoma. The p38 mitogen-activated protein kinase (MAPK) pathway is a key mediator of cytokine-induced signalling, but its role in liver injury remains elusive. In this project I propose to investigate in vivo the role of p38alpha (p38a) in experimental models of liver disease, by taking advantage of genetically modified mice with a liver-cell specific deletion of the p38a gene generated by using the Cre/loxP technology. I will analyse the function of p38a in three different models of liver disease: chemically induced hepatocellular carcinoma, liver regeneration after hepatectomy and ischemia-reperfusion injury.For these experiments I will use well-established experimental protocols and microsurgical techniques that I have already learned during my previous work. In the second part of my project, I propose to generate a new knock -in mouse line that will facilitate the conditional in vivo replacement of p38a with a mutated kinase-dead version of this protein. By generating this mouse line it will be possible to conditionally ablate the activity of p38a rather than deleting the whole protein, thus avoiding unwanted compensation from the other members of the p38a family. Using this approach it will be possible to resemble the effect of a pharmacological inhibition of p38a, much closer than a knockout of the gene can do.By combining advanced technology in mouse genetics with clinically relevant experimental models of liver injury, these experiments will clarify the function of p38 signalling in liver disease and will contribute to the better understanding of the molecular mechanisms involved in liver disease pathogenesis. The results might prove very valuable for the future development of drugs targeting the p38 MAPK pathway and their application in liver diseases in human patients.
Original text from CORDIS.
Participants
- EUROPEAN MOLECULAR BIOLOGY LABORATORY · HEIDELBERGCoordinatorGermany
Links
Data: CORDIS, © European Union