Growth factor, hormone, and nutrient regulation of liver regeneration.
The principal focus of the laboratory is to define the mechansims, both stimulatory and inhibitory, that control the regeneration of liver. The regenerating liver is used as a model in which to study the cellular and molecular mechanisms of growth control in a normal, non-neoplastic tissue. The critical issues to be understood in the process are: which signals sense the acute loss of liver mass and initiate regenerative growth; which signals maintain the differentiated functions of the liver during proliferation, and which signals stop liver growth when it has reached its appropriate mass? We aim to identify the major signals that regulate regeneration, the cells and tissues in which they are generated, and the nature of the cellular and molecular cross-talk that controls them. We study these problems in whole animals, some genetically modified to overexpress or block critical regulatory molecules, and others treated with growth factors or neutralizing antibodies; in primary cultures and lines of hepatocytes and other liver-derived cells; and in subcellular fractions of cells.
A major focus in the lab is the role of EGF-like molecules in liver growth and metabolism.
Although a potent hepatic mitogen, EGF was reported long ago to have actions that both mimic and antagonize those of insulin in the liver. The EGF receptor (EGFr) is one of a family of four related tyrosine kinase receptors: EGFr, ErbB2, ErbB3, and ErbB4. Ligands of these receptors induce hetero- and homodimers and divergent downstream signaling. Adult liver expresses only EGFr and ErbB3, while fetal liver expresses EGFr, ErbB2 and ErbB3. Ligands of both the EGFr (TGFalpha, amphiregulin, epiregulin, betacellulin, and HB-EGF) and ErbB3 (heregulins or neuregulins) are expressed in liver or pancreas. The laboratory is actively investigating the proliferative and metabolic signals generated by this important system.
ErbB2, which can dimerize with either EGFr or ErbB3 is strongly expressed in fetal and neonatal liver, but is extinguished around the time of weaning, suggesting it to be a developmental switch. The model under investigation is that the ErbB receptor family transduces growth and metabolic signals in the liver, and perhaps in other tissues, and that the various ligands and receptors in this family have different actions at different developmental stages. In addition to developmental differences in ErbB receptor expression, there are also striking zonal and circadian differences in their expression, adding to the potential richness and subtlety of ErbB signaling in the liver.
Other areas of active investigation in the laboratory include the role of receptor guanylyl cyclases, the plasminogen activator system, and also of growth inhibitors in the development and regeneration of liver.