5214A HF DeLuca Biochemical Sciences Building
440 Henry Mall
Madison WI 53706-1535
B.S., M.Sc., Istanbul University, School of Pharmacy
Ph.D., Baylor College of Medicine
Postdoctoral, Harvard University
Cellular stress responses, organelle dysfunction and interaction, beta cell function and survival, diabetes
Organelle dysfunction is linked to various disease pathogenesis. The endoplasmic reticulum (ER) plays a key role for cellular homeostasis, development, and stress responsiveness. In response to cellular stress induced by toxins, unfolded proteins and inflammation the unfolded protein response (UPR), is activated. During UPR, perturbations in ER homeostasis are sensed and transduced by ER membrane localized proteins to the cytoplasm and nucleus to initiate a compensatory response. While UPR plays a critical role for cell survival during acute stress conditions, hyperactivated UPR or unresolvable stress lead to cell demise. Thus, the unfolded protein response regulates both death and survival effectors. How or when these ER membrane proteins determine whether a cell will survive or die upon ER stress remains unclear.
Type 1 diabetes (T1D) is caused by immune-mediated destruction of insulin producing pancreatic β-cells. Due to its autoimmune nature, the major focus of current experimental therapies for T1D mainly focuses on modulating the immune system function. However, we showed that the adaptive functions of the UPR were greatly reduced in β-cells of two different type 1 diabetes (T1D) mouse models and human patients during the progression of T1D. Mitigating β-cell ER stress and restoring the UPR function with a chemical chaperone, TUDCA, was able to protect mice against T1D. TUDCA is currently in Phase I clinical trials for T1D patients.
Although this study provided the first direct link between the UPR and T1D pathogenesis, the β-cell specific function of the UPR sensors, their downstream targets, interactions with other organelles and the molecular mechanisms by which the UPR regulates pancreatic β-cell death/survival during T1D progression still remain largely unknown. Our laboratory uses biochemistry, cell biology, genetics, omics, imaging, bioinformatics, immunology as well as sophisticated genetic and pharmacological tools to understand β-cell specific functions of the stress responses, and interorganellar communication during the initiation and progression of diabetes.
Areas of Expertise
- Biomolecular Folding & Interactions
- Cell Structure & Signaling
- Immunology & Virology
- Membrane Dynamics & Proteins
- Metabolism & Endocrinology