Engineering cell lines to identify regulators of the unfolded protein response

Cellular stress signaling is critical in various chronic diseases, including cancer, neurodegenerative disease, obesity and diabetes. One of the central stress signaling pathways in the cell that is hijacked in disease states is the unfolded protein response (UPR). There are three major signaling branches of the UPR that collectively help the cell to mount a stress response, or cell death pathways if the stress cannot be neutralized. Recent research has shown that UPR plays critical roles in disease states and thus efforts are under way to target UPR for potential therapy. Using the CRISPR/Cas9 genome editing tool, we have generated UPR reporter human cell lines where all three arms of UPR can be monitored simultaneously by selective and differential fluorescent protein expression. These cell lines can be utilized to identify UPR regulators that are relevant to disease states, such as proteins, chemicals, and viruses; furthermore, they can be used in screening schemes to identify small molecule drugs that specifically inhibit or activate distinct branches of UPR. Our goal in this project is to establish proof-of-principle for the technology, develop a patentable invention and set the basis for a full verification application. The product will be significant not only for cancer, but would also be relevant for a number of other chronic diseases as well.

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