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Research

Main Interests and Big Questions

Cells, tissues, organs, and organisms can adapt to a wide range of insults and this adaptive response is a central mechanism preventing disease. What happens if the adaptive mechanisms are insufficient, and cells cannot withstand toxic insults or genetic defects that cause dysfunction and damage? The U- shaped Yerkes-Dodson curve illustrates how adaptation to stress leads to enhanced performance, while persistent stress that surpasses the capacity of adaptive mechanisms decreases performance. We apply this theory to cells and organisms as a unifying theme of our work. In particular, we study the cellular and organismal response to stress in the epigenome and the secretory pathway.

  1. How do cells and organisms manage widespread changes to the epigenome?
  2. Is there a cell surveillance mechanism to prune cells with epigenetic damage from developing embryos or mature tissues?
  3. How does activation of the endoplasmic reticulum (ER) stress response pathway (the unfolded protein response) alter lipid metabolism?
  4. Is enhanced metabolic capacity a direct target of the ER stress response?

Approaches

Our lab uses zebrafish to understand liver development and disease. We focus on developing an understanding of the molecular basis of fatty liver disease and hepatocellular carcinoma. We are dissecting how endoplasmic reticulum stress and activation of the unfolded protein response (UPR) contributes to fatty liver disease, and have pioneered the use of zebrafish to study alcoholic liver disease.  Another interest is how the epigenetic regulation of gene expression mediated by UHRF1 contributes to hepatocyte proliferation. We have developed several zebrafish models of fatty liver disease and of liver cancer and, established both cellular imaging and genomic approaches to uncover the essential pathways and key drivers that give rise to these pathologies. Collaboration is integral to our work, and our collaborations allow us to interrogate the key findings from zebrafish to identify those that are most relevant to humans.