We have made significant progress in determining the role of ?-catenin in hepatic development, zonation, liver regeneration (LR) &liver injury. Wnt/??-catenin signaling is an important contributor in hepatic zonation regulating the expression of glutamine synthetase (GS) and cytochrome P450's like CYP2E1 &1A2 in hepatocytes around central vein. We have shown ?-catenin signaling as one of the key mechanisms essential for initiation of LR. Hepatocyte-specific ?-catenin knockout mice (Hep??-cat KO) lack zonation and show delay in LR after partial hepatectomy (PHx) due to decreased expression of cyclin-D1. In addition, ?-catenin overexpression promotes LR in mice and in acetaminophen toxicity patients. Several additional key questions emerge from the previous studies &form the basis of current proposal. What are the upstream effectors and their cell sources that regulate ?-catenin activation in normal liver for zonation and during LR for hepatocyte proliferation and who is ?-catenin signaling turned off once LR is accomplished. Lastly, are there clinically relevant molecules that can be used to induce??-catenin signaling to provide proof-of-principle that ?-catenin activation can have implications in treatment of end stage liver disease (ESLD). We hypothesize that Wnts from varying cell sources act in autocrine or paracrine mechanisms to direct ?-catenin activation to in turn instruct hepatic zonation and hepatocyte proliferation during LR, and their elucidation will have broad therapeutic impact. Based on our preliminary studies in mice where Wnt co-receptors LRP5/6 have been deleted from hepatocytes (Hep-LRP5/6 KO) that lack zonation and show delay in LR, ?-catenin appears to be under exclusive control of Wnt signaling in vivo in liver. Also, mice with hepatocyte-specific deletion of Wntless (Wls), essential for Wnt secretion from a cell, do not show impaired zonation or initiation of LR, but displayed prolonged LR after PHx.
In specific aim 1, we will determine cellular origin &molecular identity of upstream effectors of ?-catenin in liver zonation and during LR process. This will be done by characterizing these two processes in mice that conditionally lack Wls in various cells of the liver including hepatocytes, sinusoidal endothelial cells, Kupffer cells and stellate cells using cell-specific Cre transgenic lines and floxed-Wls mice that exist in our lab.
n specific aim 2, we will determine the mechanism of termination of ?-catenin signaling following accomplishment of hepatocyte proliferation during LR after PH. Hep-Wls KO mice exhibit continued expression of cyclin-D1, cell proliferation at 72-96h after PHx &decreased Wnt5a, an inhibitory Wnt. We will investigate how Wnt5a inhibits ?-catenin signaling in hepatocytes both in vitro and in vivo. We will also use Hep-Wnt5a KO mice to conclusively address if Wnt5a indeed terminates ?-catenin signaling and eventually LR after PHx.
In aim 3, we propose to study the therapeutic efficacy of Wnt stimulation to augment LR in murine models of ALF. Our preliminary data shows that ?-catenin activation can promote LR. We identify triiodothyronine (T3) to stimulate ?-catenin signaling in PKA-dependent manner to induce hepatocyte proliferation. We will conclusively address the relevance of PKA-dependent ?-catenin activation in T3-induced hepatocyte proliferation using Hep-LRP5/6 KO mice. We will directly evaluate efficacy of T3 and its thyroid receptor- ? selective analogue GC-1, in inducing LR in acetaminophen-induced liver injury and 90% PH models of acute liver failure. Thus our proposed studies will further our understanding of cellular and molecular basis of LR and investigate the utility of ?-catenin stimulation as a way to treat ESLD using clinically relevant agents.
The research proposal focuses on ?-catenin-directed personalized medicine in hepatic regenerative medicine as a treatment strategy for end stage liver disease (ESLD). The studies will address the cellular and molecular mechanisms of ? -catenin activation during liver regeneration. Proposal will also test the efficacy of relevant agens to stimulate ? -catenin signaling as a possible treatment of ESLD in preclinical models.
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