The Hippo signaling pathway is a fundamental regulator of organ growth and homeostasis. Specifically, the downstream effector of this pathway, Yap (and its homolog Taz), has been implicated in the maintenance of stem cells and in the regulation of liver size. Although under normal physiological conditions, hepatocytes serve as the main source of cell replenishment in the liver, certain surgical and chemical injury conditions have been shown to cause the expansion of atypical ductal progenitor cells. In previously published work, we have shown that modifications in Yap expression can reprogram hepatocyte to a ductal phenotype, however the nature of how Yap activity regulates biliary ductal progenitors in native conditions within the liver is currently unknown. I have shown that Connective Tissue Growth Factor (CTGF), one of the most widely characterized targets of the hippo-signaling pathway and a bona-fide reporter for Yap transcriptional activity, is expressed heterogeneously in ductal progenitor cells in the liver. Additionally, I have shown that Yap activity is required for organoid initiation and growth in three-dimensional cultures. Finally, I have also shown that Yap activity is upregulated in expanded ductal cells after chemical injury. The overarching goal of this proposal is therefore to investigate how Yap and Taz regulate and maintain liver ductal progenitor cells. It also hopes to identify the role of Yap and Taz in the ductal response to well-established liver injury models. Through my continued research on this project, I hope to take advantage of all of the resources available to me at Boston Children's Hospital and Harvard University. Additionally, I hope to continue developing as a scientist and gathering knowledge in the area of tissue regeneration and organ maintenance. As can be seen in the work I have already performed for this proposal and for the work that I will continue to do, I am committed to a scientific career where I will be devoted to advancing basic science to directly impact human health. This proposed work will hopefully contribute to a broader understanding of cellular maintenance in the liver and the mechanism by which the liver responds to injury. The isolation and examination of liver progenitor cells that can be cultured indefinitely in-vitro (and the downstream mechanisms by which these cells are maintained), may also pave the way for cellular therapies for liver disease. Additionally, this work may help furthe our understanding of the basic processes and cellular maintenance required for the upkeep of a vital organ in our bodies.
The adult liver has a remarkable ability to regenerate and under certain injury conditions, it has been shown that the liver activates ductal progenitor cells to respond. Since, the Hippo Signaling pathway is vital for maintaining stem cells in adult organs and has been shown to regulate liver cancer, it is imperative to understand the role of this pathway in controlling the regeneration and preservation of the adult liver. In this proposal, I wil utilize mouse models, genetic tools, and cell culture techniques to address the role of Hippo Signaling in the regulation of adult ductal progenitors in the liver.
