My research interests focus on bridging the gap between systems biology and cell biology. My long termgoal is to couple my expertise in cell biology of the endoplasmic reticulum (ER) with high throughput toolsand novel analytical methods to create a model for a self-contained unit within the cell. In the short term Iplan to focus on the genes essential for maintaining homeostasis in the ER. The importance of a robustlyfunctioning ER is underscored by its requirement for the normal development of multicellular organisms,especially differentiation of dedicated secretors such as plasma cells and insulin-secreting pancreas cells.To gain novel insights on maintenance of homeostasis in the ER, I propose to screen for all genes in whoseabsence the ER accumulates unfolded proteins. This can be measured accurately by utilizing a reporter forinduction of the ER stress induced Unfolded Protein Response (UPR). Once all genes will be identified, Iplan to make a quantitative and accurate genetic interaction map,showing the extent by which a mutation inone of these genes changes the phenotype of all the others. Based on previous work, I believe that analysisof this map will allow me to predict functions for unknown proteins as well as organize all proteins intocomplexes and pathways. It will also allow me to study the hierarchy of the different processes involved inmaintaining a fully functional ER. I propose to do this both in yeast (by using the yeast deletion strain libraryand a novel library of hypomorphic alleles of essential genes) and human cells (using RNAi technology). Thiscomparison should allow me to define the evolutionary constraints leading to conservation of the organellefunctioins, thus developing a new understanding of the secretion process and its players in eukaryotes.Summery: All secreted and membrane-bound proteins essential for cellular communication and reaction tothe environment are first translocated into the endoplasmic reticulum (ER) where they fold and mature intotheir native conformations aided by a variey of folding enzymes. A change in conditions in the ER causesactivation of a stress response that mediates return to homeostasis. Mutations causing this response to beoveractive or underactive have been reported to play a role in diseases as varied as cancer, cystic fibrosis(CF), diabetes, neurodegeneration and heart disease. Thus, gaining a deeper understanding of the genesregulating homeostasis in the ER and the stress response will allow us to treat such human pathologies.
