Pancreatic beta cell failure plays a central role in diabetes which affects over 285 million people worldwide. In beta cells, the endoplasmic reticulum (ER) is a central subcellular organelle to produce insulin. In health, beta cell ER homeostasis is maintained by the delicate balance between protein synthesis, folding, ER export and degradation. Disruption of ER homeostasis, by genetic and environmental factors, causes beta cell death and triggers diabetes. Our research focus is to understand, using systems biology approaches, how ER homeostasis is disrupted in diabetes. The ultimate goal is to identify new therapeutic targets to restore ER homeostasis and improve beta cell survival in diabetes. Currently, our lab is working on the following projects with funding support from NIH and other foundations:
- Quantitative proteomics analysis of perturbed ER homeostasis in diabetes ER homeostasis is maintained by a complex proteostasis network. In spite of the essential role of beta cell ER in insulin biogenesis and diabetes, its protein composition was not systemically analyzed before. We conducted the first comprehensive proteomic analysis of the beta cell ER proteome. This highly informative dataset containing 1467 protein identifications was published in Proteomics May, 2015. We are currently studying how key ER proteins are altered in diabetes and then we will target these proteins for therapeutic interventions to restore ER homeostasis.
- COPII dependent ER export of proinsulin in beta cells ER export was the least understood process in ER homeostasis. To fill this knowledge gap, I learned the in vitro COPII (coat protein complex II) vesicles reconstitution technique from Dr. Randy Schekman’s lab. We applied this assay in beta cells and established the molecular mechanism by which proinsulin exits the ER. Furthermore, we found defective ER export could lead to beta cell apoptosis. Our original work was published in June, 2015 in Molecular Endocrinology. Based on this initial work, we are studying how COPII dependent ER export is disrupted in diabetes and how to rescue such a defect with therapeutic interventions.
- Development of quantitative and targeted proteomics technologies Our lab has been actively developing and implementing iTRAQ-based and LC-SRM based quantitative proteomics technologies in our own projects as well as helping other investigators at SOM, WSU and other institutions.