Grant: Operating Grant - PA: Genetics (Bridge Funding: Research Priorities)

Most cells in our body are polarized with distinct membrane compartments with distinct functions (e.g. neurons or epithelial cells). We are interested in the cellular processes that target membrane proteins to the correct membrane compartments. Targeting a protein to the wrong membrane compartment can have dire health consequences. For example, in polycystic kidney disease, sending the Epidermal Growth Factor Receptor (EGFR) to the wrong membrane in kidney epithelial cells can result in the formation of cysts and subsequent organ dysfunction. The objective of this proposal is to understand how genes and gene products (proteins) function to regulate protein localization in epithelial cells. To study how membrane proteins are targeted to the correct membrane in live animals, we are using the nematode Caenorhabditis elegans. C. elegans EGFR needs to localize to the correct membrane compartment of epithelial cells to transmit a signal necessary for the development of the hermaphrodite vulva, an organ essential for egg-laying. We have the tools to monitor EGFR localization in live animals using microscopy. The powerful genetics of C. elegans permit us to identify and study the genes that regulate EGFR localization during vulva induction. In this proposal, we will determine how several genes, specifically those coding for Arf and Rab GTPases that regulate membrane trafficking processes, work together to regulate EGFR localization. Understanding the cellular processes that regulate EGFR localization in this simple genetic model organism, will reveal conserved fundamental mechanisms that regulate membrane protein localization in human cells. Since membrane trafficking is a fundamental cellular process, many of the genes we study are linked to human disease including neurodegenerative disease and cancer. The results of this study will provide better understanding of their functions which can be applied to understand disease etiology.