Projects per year
A major mediator of hepatocyte regeneration following partial hepatectomy is Hepatocyte Growth Factor (HGF), whose receptor is a membrane tyrosine kinase known to activate the lipid kinase phosphatidylinositol 3'-kinase (PI 3'-kinase) in HGF-stimulated cells. This Pilot and Feasibility study will examine the role of PI 3'-kinase during hepatocyte proliferation, using, the minimal deviation rat hepatoma line Fao as a model system. Fao cells retain many liver- specific functions. Moreover, Fao cells can be moved from a quiescent state into a proliferative state by the addition of insulin in the absence of serum or other growth factors. As insulin shares with HGF the ability to activate PI 3'-kinase, these cell provide a useful model system in which to study the regulation of hepatocyte proliferation. The approach use in this proposal is to modulate the activity of PI 3'-kinase in Fao cells through the introduction of activated or dominant negative mutants; alterations in insulin- stimulated PI 3'-kinase activity will be correlated with changes in the sensitivity of insulin-induced mitogenic responses. Activated PI 3'-kinase mutants will be created by introducing sequences that direct the addition of lipid moieties, thereby causing the constitutive association of PI 3'-kinase with intracellular membranes. Dominant negative mutants will be created by mutating residues in the regulatory and catalytic subunits of PI 3'-kinase that are homologous to critical residues in related proteins. The effect of these perturbations on insulin-stimulated proliferation, as well as insulin stimulation of liver-specific metabolic enzymes, will be determined. These studies should be a valuable initial inquiry into the role of PI 3'-kinase in hepatocyte physiology.
|Effective start/end date||10/1/93 → 9/30/98|
- National Institute of Diabetes and Digestive and Kidney Diseases
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- 1 Finished
Liver Pathobiology and Gene Therapy Research Core Center
Gupta, S., Rogler, C. E., Roy-Chowdhury, J., Satir, P., Shafritz, D. A., Wolkoff, A. W., Rogler, C. C. E., Shafritz, D. D. A., Shafritz, D. D., Satir, P., Gupta, S. S., Snapp, E. L., Wolkoff, A. W., Backer, J. M., Roy-Chowdhury, J., Czaja, M. J., Davidson, A., Goldfischer, S., Hays, R., Horwitz, S., Krauter, K., Meier, T. U., Reid, L. M., Rogler, C., Rogler, L., Satir, B. & Stanley, P.
National Institute of Diabetes and Digestive and Kidney Diseases
6/1/89 → 5/31/21
Project: Research project