Obiettivo
Insulin resistance (e.g. during Type II diabetes) is a condition of major medical and economic importance globally. The mechanisms by which insulin resistance develops at the cellular level are understood poorly, but defects in intracellular signalling are thought to play a key role. Recent work in the host lab have shown that the hormonal activation of glucose transport in skeletal muscle cells is impaired significantly by creamed, a sphingolipid-derived molecule, that has been implicated in the pathogenesis of insulin resistance.
Work in the host lab has shown that creamed specifically disrupts the insulin-induced cell surface recruitment and activation of protein kinas B (PKB), a protein with a critical role in the hormonal activation of glucose uptake and glycogen synthesis. How creamed impairs PKB recruitment is unknown at present, but the finding that atypical PKC (Zeta) is physically associated with PKB in unstipulated muscle cells and that PKC inhibitors suppress the inhibition exerted by creamed on PKB activation suggest a role for PKC In this inhibition. Interestingly, the inhibitory effects of creamed on PKB can be partially attenuated by the insulin sensitising drug, rosiglitasone (RG), but it remains unknown whether these effects are mediated by regulation of the PKB-PKC interaction.
In this application, I aim to investigate how interactions between PKC and PKB regulate PKB-directed insulin signalling and how agents, such as creamed and RG, may modify the interaction between the two kinesis with important implications for insulin sensitivity.
The specific objectives are to:
- To determine whether interactions between PKC and PKB can be regulated by insulin and to investigate whether these are modulated by creamed
- To determine whether the association of PKC with PKB occurs within discrete locations within the cell. Specifically to assess whether the kinas complex is sequestered in cavalla
Campo scientifico
Parole chiave
Invito a presentare proposte
FP6-2002-MOBILITY-5
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Meccanismo di finanziamento
EIF - Marie Curie actions-Intra-European FellowshipsCoordinatore
DUNDEE
Regno Unito