Careful analysis of the biology of livers ofthe PiZ mice carrying a transgene for ATZ (the misfolded A1 AT protein) demonstrates that ATz expression is not uniform across all hepatocytes. The degree of ATZ expression and size of the ATZ globules varies dramatically between hepatocytes, and in some of them there is no expression at all, even though they all carry the same transgene. In addition, hepatocytes that have spontaneously shut down the ATZ transgene enter into proliferation and over time, in many instances, replace the entire hepatocyte population. If there was an understanding of what controls expression of the ATZ transgene and what shuts it down, one may be able to design rational strategies with application to humans that would decrease or eliminate expression of ATZ. In addition, hepatocytes not bearing ATZ globules have a capacity to proliferate at high rates. It is not clear whether this is a cause or an effect of absent ATZ expression and the forces/mechanisms driving proliferation of the globule-free (GF) cells are not understood.
Aims 1 and 2 will explore the levels and effects of growth factors and cytokines associated with liver regeneration (HGF/Met, EGFR signaling, TNF, IL6, etc.) between PiZ and wild-type mice and to compare the effects of these on GF and globule-containing (GC) hepatocytes, in order to detect differences in regenerative factors between the two types of m ice and how they affect spontaneous liver repopulation by GF cells. In addition, we will explore the effect of delivering characterized biologic or chemical agents stimulating liver growth or regeneration and observe whether that effect alone is sufficient to accelerate conversion of GC to GF cells.
Aim 3 will focus on details of differences in gene expression between GF and GC cells, with emphasis on expression of growth or apoptosis related genes, in order to. obtain a global view of the impact of ATZ globules on the cell physilogy of the hepatocyte.
Aim 4 will delve into the mechanisms controlling expression of the ATZ transgene in the PiZ mice by examining relationships between the transgene promoter and proteins/transcription factors that populate the promoter region.
The studies are highly relevant for understanding the biology of Al AT in the human liver. Each one of the aims has the potential of delivering results with potential therapeutic implications. Chemical mitogens, growth factors and cytokines that may alter the balance between GC and GF hepatocytes can be delivered to humans. The gene expression differences and promoter functions in GC and GF cells may also allow for precise control of expression of ATZ thus rescuing human livers from the impact of ATZ accumulation.
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