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 | Feroz Papa, M.D., Ph.D.
Assistant Professor of Medicine When proteins misfold and aggregate within cellular compartments, cells can become damaged. Such protein misfolding is now recognized as a primary 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 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 eventually triggering apoptosis if the stress is not alleviated. Numerous studies now show that pancreatic islet beta-cells (which produce the hormone insulin) are highly susceptible to ER stress. Building on these findings, we ask whether unchecked ER stress in beta-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 beta-cells become damaged and die, causing insulin needs to go unmet. By causing beta-cells to overwork and overproduce insulin for long periods of time, obesity and overweight conditions may be generating high levels of ER stress in these cells. Following this line of reasoning, we are inquiring whether the unfolded protein response (UPR)—a cellular homeostatic pathway triggered by ER stress—is dysregulated in type 2 diabetes, and conversely whether it may pharmacologically targeted to treat the disease. Our lab takes varied strategies to answer these questions: One approach is hypothesis-driven: We propose that ER stress promotes beta-cell death while the UPR is cytoprotective (but only up to some point), and are building ER stress-induced cellular and mouse models of diabetes in which to test this hypothesis. In these cell and animal systems we use novel tools we have developed to measure and reduce ER stress in large populations of individual, living beta-cells. By scoring beta-cell death and development of diabetes through these manipulations, we seek quantitative answers to the questions: how dangerous is ER stress for the beta-cell, and how much protection does the UPR afford?Type 2 diabetes has become pandemic, yet because key details of its pathogenesis are not understood, therapeutic options remain limited. If our work helps elucidate the cause of type 2 diabetes, it may lead to novel, rational, and more effective therapies for this disease, as well as other protein misfolding diseases. Selected publication(s): F.R. Papa, C. Zhang, K. Shokat, and P. Walter. “Bypassing a Kinase Activity with an ATP-competitive Drug” Science 302, 1533-1537 (2003). D.J. DeMarini, F.R. Papa, S. Swaminathan, D. Ursic, T.P. Rasmussen, M.R. Culbertson, and M. Hochstrasser. "The Yeast SEN3 Gene Encodes a Regulatory Subunit of the 26S Proteasome Complex Required for Ubiquitin-Dependent Protein Degradation in vivo ". Mol and Cel Bio 15, 6311-6321 (1995). F.R. Papa and M. Hochstrasser. "The Yeast DOA4 gene Encodes a Deubiquitinating Enzyme Related to the Human tre-2 Oncogene". Nature 366, 313-319 (1993). |
