NSF Postdoctoral Fellowship in Biology FY 2021: Translating transcriptome to phenome: defining intercellular signaling landscapes of the liver

Mccray, Tara, Seattle WA

Investigators

Abstract

This action funds an NSF Postdoctoral Research Fellowship in Biology for FY 2021, Integrative Research Investigating the Rules of Life Governing Interactions Between Genomes, Environment and Phenotypes. The fellowship supports research and training of the Fellow that will contribute to the area of Rules of Life in innovative ways. One of the most fundamental rules of life is the “central dogma” and states that DNA is the genetic code for proteins. As the activity of thousands of proteins have been identified, the next rule of life needs to define how these overlapping protein signals resolve to control cells and build tissues. This research aims to understand how cells use multiple redundant pathways to talk to one another and achieve a particular outcome. In short, this research will expand upon the established central dogma and enhance scientific understanding of how cell signaling networks are integrated. While doing so, this research will advance scientific technology in spatial transcriptomics and organoid engineering with far reaching applications in disease models and drug toxicity testing. This research will also broaden the participation in STEM through mentorship and outreach opportunities for underrepresented minorities in the University of Washington surrounding community. The next rule of life should establish how numerous cell signaling cascades achieve a predictive phenotype. Using the regenerating liver as a model phenotype, this research will determine the biological signals and their originating intercellular sources that drive that phenome. Human liver tissue and bioengineering human liver grafts will be studied using single cell RNA sequencing and spatial transcriptomics to create a ‘blueprint’ of liver cell signaling networks. These networks will be reconstructed in vitro through an engineered novel human liver organoid coculture model. To mimic the cell:cell interactions in native tissue, human primary liver epithelial organoids will be cultured alongside their in vivo neighbors, endothelial and fibroblast cells. Finally, cell signaling networks will be examined within the cocultured organoids in vitro and in in vivo grafts to prove their involvement in liver regeneration. Components of individual signaling networks will be probed to determine their contribution to the liver regeneration phenotype and develop a predictive rule of life. These research findings will be communicated through training opportunities such as teaching, conference presentations and publications. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.