In this K01 application, I will get mentorship and protected research time to grow my skill repertoire to pursue becoming a principal investigator in the field of gastric epithelial biology. My career development will be nurtured through weekly meetings with Dr. Mills and Dr. DiPaolo, through convening an experienced senior advisory committee, and opportunities for professional development through WashU and the NIH. Skill development focus will include, but are not limited to, manuscript/grant preparation, seminars and courses described in the career development section, and presentations at international conferences (DDW, FASEB, etc.). Training includes coursework in biostatistics, workshops on bioinformatics, continued training in bioethics, and participation diverse seminar series that will include me giving presentations, interacting with visiting outside speakers, and attending journal clubs. The overarching hypothesis of this project is the following: The Hippo pathway is a central regulator of gastric epithelial homeostasis and response to injury. We propose to address these Specific Aims with regards to the role of the Hippo pathway in the gastric epithelium: 1) To address the sufficiency/necessity of the Hippo pathway in maintaining normal, mature gastric epithelium cell identity during homeostasis and following injury and the molecular pathways the interact with the Hippo pathway in driving acute dedifferentiation phenotypes (gene expression, cell shape, cell proliferation). 2) To describe the role of the Hippo pathway in gastric organoid growth and stemness. We will also address discovery of novel regulated and direct targets of YAP1/TAZ in this in vitro metaplasia model.
This research project and training plan will provide advanced training in bioinformatics/biostatistics (for scRNA-seq, RNA-seq, and ChIP-seq), organoid culture, Helicobacter pylori infection, and High-content imaging to explore the regulation of cell identity and growth in differentiated cells of the gastric epithelium. The studies proposed in this application will provide key insights into how gastric cell identity is maintained, controlled, and perturbed in disease states.
