Feroz Papa, MD, PhD

Professor
Department of Medicine
Division of Endocrinology and Metabolism
Research Overview: 

My lab, which is based in the UCSF Diabetes Center and the California Institute for Quantitative Biosciences (QB3), uses molecular, cellular, and organismal approaches to address broad questions revolving around protein misfolding and disease.

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 cellular suicide 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 becoming clear that type 2 diabetes develops in an individual when a critical number of his or her beta-cells become damaged and die, and the resulting imbalance causes 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: 
We hypothesize that ER stress promotes beta-cell death while the UPR is cytoprotective (but only up to some point). In order to test these concepts rigorously, my lab is pioneering new single-cell stress measurement and adjustment devices. Two particular examples of such tools are highlighted (see publication list below): Using new redox-responsive green fluorescent protein (GFP) reporters we can measure changes in ER redox potential under ER stress. This informs us when homeostatic control through the UPR has become lost. Reciprocally, we have devised systems to adjust the output of the UPR—irrespective of ER stress—through chemical-genetic manipulation of the UPR sensor/effector IRE 1alpha using small molecules. Using these novel tools we hope to gather quantitative answers to the questions: how dangerous is ER stress for the beta-cell, how much protection does the UPR afford, and at what thresholds do UPR outputs become destructive rather than adaptive? Extending these concepts into human populations, we are interested in developing biomarkers in humans for predicting risk for type 2 diabetes, and validating targets for intervention and disease modification.

Type 2 diabetes has become pandemic, yet because key details of its pathogenesis are not yet clearly understood, therapeutic options remain limited. It is our hope that by helping elucidate the cause of type 2 diabetes, our work may eventually identify targets for disease modification and lead to novel, rational, and more effective therapies for this disease, as well as other protein misfolding diseases.

Primary Thematic Area: 
Tissue / Organ Biology & Endocrinology
Secondary Thematic Area: 
Developmental & Stem Cell Biology
Research Summary: 
Protein misfolding diseases and novel therapies

Websites

Publications: 

nAChR signaling regulates IRE1a activation to protect ß cells against terminal unfolded protein response under irremediable ER stress.

Journal of diabetes investigation

Ishibashi T, Morita S, Kishimoto S, Uraki S, Takeshima K, Furukawa Y, Inaba H, Ariyasu H, Iwakura H, Furuta H, Nishi M, Papa FR, Akamizu T

Parallel signaling through IRE1a and PERK regulates pancreatic neuroendocrine tumor growth and survival.

Cancer research

Moore PC, Qi JY, Thamsen M, Ghosh R, Peng J, Gliedt MJ, Meza-Acevedo R, Warren RE, Hiniker A, Kim GE, Maly DJ, Backes BJ, Papa FR, Oakes SA

Development of a Chemical Toolset for Studying the Paralog-Specific Function of IRE1.

ACS chemical biology

Feldman HC, Vidadala VN, Potter ZE, Papa FR, Backes BJ, Maly DJ

Small Molecules to Improve ER Proteostasis in Disease.

Trends in pharmacological sciences

Gonzalez-Teuber V, Albert-Gasco H, Auyeung VC, Papa FR, Mallucci GR, Hetz C