Numerous recent studies link development of type 2 diabetes (T2D) to endoplasmic reticulum (ER) stress, a condition that occurs whenever protein-folding requirements overwhelm protein-folding capacity in the secretory pathway. Notably, there is mounting evidence that ER stress contributes to diminished glucose-responsive insulin secretion in ?- cells, to?-cell apoptosis, and to generalperipheral insulin resistance, all hallmarks of T2D. ER stress triggers the unfolded protein response (UPR) pathway, which slows translation and transcriptionallyupregulates genes that enhance ER protein-folding capabilities. If homeostasis is not restored through these outputs, the UPR triggers apoptosis instead. We hypothesize that key component of the UPR, act as a toggling switches between homeostatic and apoptotic outputs, ultimately controlling ?-cell fate. Our project goal is to study these switches at the molecular level using interventional approaches.
Type 2 diabetes mellitus (T2D) affects 18 million Americans, with national healthcare and lost productivity costs exceeding $100 billion per year. T2D begins as a state of compensated insulin resistance;frank disease develops when approximately 50% of insulin-producing pancreatic islet ?-cellsof affected individuals undergo cell death. A detailed understanding of how ?-cells die is necessary to rationally mount an assault on T2D. We hypothesize that the stress from having to overwork may be responsible for ?-cell death in T2D. In this proposal we are testing this concept using molecular and cellular approaches.
|Morita, Shuhei; Villalta, S Armando; Feldman, Hannah C et al. (2017) Targeting ABL-IRE1? Signaling Spares ER-Stressed Pancreatic ? Cells to Reverse Autoimmune Diabetes. Cell Metab 25:883-897.e8|
|Feldman, Hannah C; Tong, Michael; Wang, Likun et al. (2016) Structural and Functional Analysis of the Allosteric Inhibition of IRE1? with ATP-Competitive Ligands. ACS Chem Biol 11:2195-205|
|Ghosh, Rajarshi; Wang, Likun; Wang, Eric S et al. (2014) Allosteric inhibition of the IRE1? RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158:534-48|
|Maly, Dustin J; Papa, Feroz R (2014) Druggable sensors of the unfolded protein response. Nat Chem Biol 10:892-901|
|Upton, John-Paul; Wang, Likun; Han, Dan et al. (2012) IRE1ýý cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. Science 338:818-22|
|Wang, Likun; Perera, B Gayani K; Hari, Sanjay B et al. (2012) Divergent allosteric control of the IRE1? endoribonuclease using kinase inhibitors. Nat Chem Biol 8:982-9|
|Lerner, Alana G; Upton, John-Paul; Praveen, P V K et al. (2012) IRE1? induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab 16:250-64|
|Shore, Gordon C; Papa, Feroz R; Oakes, Scott A (2011) Signaling cell death from the endoplasmic reticulum stress response. Curr Opin Cell Biol 23:143-9|
|Merksamer, Philip I; Papa, Feroz R (2010) The UPR and cell fate at a glance. J Cell Sci 123:1003-6|
|Han, Dan; Lerner, Alana G; Vande Walle, Lieselotte et al. (2009) IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138:562-75|