Notch Signaling


The aim of our study is to understand the general mechanisms of epithelial repair and regeneration. The liver is an excellent model for this study because of its ability to regenerate and for the strong impact that chronic liver disease have on health. Chronic liver diseases are the result of progressive damage to liver cells and the mechanisms of regeneration / repair that follow.
Knowledge of the repair mechanisms in chronic liver disease will give us useful information for trying to translate the liver regeneration properties in clinical applications that can preserve the organ functionality and prolong patient survival. The mechanisms that regulate liver repair are not well known, however, they seem to be a recapitulation of the liver ontogeny. Notch signaling, a well conserved mechanism during evolution, is involved in determining cell fate during development of many organs. Our recent data show that in patients with Alagille syndrome (AGS) -a congenital cholangiopaty caused by mutations in the Notch signaling- the so-called ductular reaction (which is considered the mark of the repair of the liver), is incomplete and leads to accumulation of intermediate hepatobiliary cells that express transcription factors typical of cholangiocytes. Our hypothesis is that Notch plays an important role in the repair / regeneration of the liver during adult life. To date, Notch signaling has been studied especially for its role during development while little is known about its role in adult organ physiology. In this project we will use mouse cell lines, mice carrying mutation in the Notch genes and Notch inhibitors to demonstrate the involvement of Notch in liver repair and its modulation by IFN-alpha and TNF-alpha. As a result we expect that the ductular reaction and activation of progenitor cells is impaired in conditions in which the signaling of Notch is impaired. These studies will increase our knowledge on the pathogenesis of AGS, knowledge that could also be to translated for the treatment of other cholangiopaties.