When proteins misfold and aggregate within cellular compartments, cells can become damaged. Such protein misfolding is now recognized as the cause of diverse diseases including Alzheimer's disease, the amyloidoses, and the transmissible spongiform encephalopathies. In our lab we study the molecular and cellular underpinnings of protein misfolding diseases, to develop rational, novel, and possibly more effective ways to treat these conditions.
We are particularly interested in protein misfolding that originates in the endoplasmic reticulum (ER) organelle. In many eukaryotic cells—especially those specialized to produce large quantities of secretory proteins—the ER is an extensively developed, protein-folding factory. Nevertheless, high demands to synthesize and fold secretory proteins can overwhelm the ER's capabilities, causing “ER stress”. Chronic exposure to such ER stress causes unfolded proteins to aggregate in the ER, damaging the secretory apparatus and triggering apoptosis.
Numerous studies have now shown that pancreatic islet ß-cells (which produce the hormone insulin) are highly susceptible to ER stress. Building on these findings, we wish to know whether unchecked ER stress in ß-cells leads to the common human disease type 2 diabetes. It is clear that type 2 diabetes develops in an individual when a critical number of his or her ß-cells become damaged and die, causing insulin needs to go unmet. We are inquiring whether this attrition may occur because of unremitting ER stress that cannot be contained in the ß-cells of some individuals. For instance, obesity, a condition that promotes type 2 diabetes, causes ß-cells to overwork for long periods of time, possibly generating ER stress. Following this line of reasoning, we also wish to know whether the unfolded protein response (UPR), a pathway triggered by ER stress to expand the ER's protein folding capacity, can be a natural brake on the road to type 2 diabetes.
We are taking varied strategies to answer these questions:
• One approach is classically hypothesis-driven: We propose that ER stress promotes ß-cell death while the UPR is protective, and are building ER stress-induced mouse models of diabetes in which to test this hypothesis. In these mice we will use novel tools we have developed, consisting of small molecule drugs to manipulate, and noninvasive fluorescent reporters to measure, both the UPR and ER stress as independent variables in individual cells, as we score ß-cell death and development of diabetes in these animals. With this approach we will seek quantitative answers to the questions: how dangerous is ER stress for the ß-cell, and how much protection does the UPR afford?
• Simultaneously, we have initiated high-throughput (HTS) drug screens designed to yield novel effectors of druggable UPR targets that we have identified. In particular, the ER stress-sensor Ire1 presents an attractive target because we have already shown that manipulation of Ire1's kinase domain with small molecule ligands can modulate the entire UPR. We will aim to use any UPR-specific small molecule drugs we identify through such screens to further refine our understanding of how cells cope with ER stress.
Type 2 diabetes has reached epidemic levels worldwide, yet because key details of its pathogenesis are not understood, our therapeutic options remain limited. We are hopeful that if our work helps elucidate the cause of type 2 diabetes, it may lead to novel, rational, and more effective therapies. In addition, we expect that this work will yield important general insights into how professional secretory tissues adapt to ER stress. As such, we hope that our approaches will prove to be generally useful for studying other protein misfolding diseases.
Biomedical Sciences (BMS) Graduate Program
