Project: Research project

Project Details


The overall objective of this proposal continues to be to define the critical cellular mechanisms culminating in
lethal liver cell injury. Because of the importance of cholestatic liver injury in human disease, our program is
working on the cellular mechanisms causing hepatocyte injury during cholestasis. Specifically, our long-term
goal is to understand the cellular mechanisms by which bile salts, which accumulate in the liver during
cholestasis, modulate hepatocyte apoptosis. Based on our preliminary data, we propose the novel CENTRAL
HYPOTHESIS that hvdrophobic hepatotoxic bile salts induce hepatocvte apoptosis by a Fas-dependent
mechanism while more hydrophilic bile salts inhibit apoptosis by actively stimulating a phosphoinositide
3-kinase (PI3K)-dependent survival pathway. We will now employ current and complementary molecular,
biochemical, and cell biological approaches to ascertain how bile salts modulate apoptotic effector processes.
Our proposal has three SPECIFIC AIMS. FIRST, we will directly test the hypothesis that toxic bile salts
induce hepatocyte apoptosis by a Fas-dependent process resulting in: a) Fas oligomerization independent of
Fas ligand;and b) formation of a death-inducing signaling complex (DISC) with caspase 8 activation.
SECOND, we will test the hypothesis that toxic bile salts increase plasma membrane Fas receptors: a) by a
mechanism dependent upon a redistribution of pre-existing cytoplasmic Fas to the plasma membrane via a
microtubule-dependent transport pathway;and b) resulting in a mechanism of apoptosis dependent upon
intracellular Fas translocation to the cell surface. FINALLY, non toxic, hydrophilic bile salts directly signal
cell survival pathways by a phosphoinositide 3-kinase (PI3K)-dependent mechanism resulting in: a) activation
of the antiapoptotic atypical protein kinase c isoforms (PKC[unreadable] and PKCX.);and b) inhibition of apoptosis by
atypical PKC-dependent activation of nuclear factor kappa B (NF-KB) and/or caspase phosphorylation. The
proposal is innovative conceptually and technically as it tests new concepts for both bile salt-mediated
cytotoxicity and apoptosis in general using sophisticated methodologies. The significance of the information
generated is that it will help provide a framework for the potential development of novel therapeutic strategies
effective in attenuating cholestatic liver injury.
StatusNot started


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