Feroz Papa, MD, PhD

Associate Professor of Medicine
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My research lab at UCSF studies a class of human diseases that are caused from the premature death of overworked cells in our bodies. Over the last few years we have learned that when cells overwork, they experience a unique form of stress within a part of the cell called the “endoplasmic reticulum (ER).” This type of cellular stress has been named ER stress by scientists. If ER stress is not corrected, and continues for too long, it causes the affected cells to die prematurely. Depending on the type of cell that dies under high ER stress, the cell loss results in the development of various deadly diseases. We and other scientists have found evidence that type 2 diabetes is an example of an important human disease caused by ER stressType 2 diabetes occurs in a patient when his or her insulin-producing pancreatic cells die prematurely. Research shows that the pancreatic cells suffer ER stress and die when they are forced to overwork and overproduce insulin under conditions of obesity and/or over-consumption of carbohydrates.

We are experiencing a pandemic of type 2 diabetes. The disease currently affects 25 million Americans and 300 million people across the world. These numbers are projected to greatly increase over the next decade, especially in Latin America, Asian countries, and Sub-Saharan Africa. The costs of treating type 2 diabetes are astronomical and soaring. In 2010 alone, the direct and indirect costs to the United States economy from type 2 diabetes were greater than $100 billion, and these costs are projected to triple in a decade. Type 2 diabetes causes great human suffering, leading to a spectrum of complications ranging from blindness, kidney failure, and limb amputations, to premature death of patients from heart attacks and stroke. These typical complications of diabetes are caused by high blood sugar levels as the pancreatic cells die and insulin levels fall. Current therapies range from drugs that sensitize the body to its remaining insulin, to replacement of insulin itself. However, none of the current therapies work very well to stop progression of the disease once it has started.

Perhaps these treatments fail to work  because they do not target the root cause of the disease—death of the overworked pancreatic cells. Therefore, the rapidly accumulating knowledge that ER stress is an important cause of type 2 diabetes may provide us with new opportunities to attack this deadly disease. Recently labs in our field have learned much about what causes the ER stress cell death process, and how to reduce the death process with drugs. We are currently testing whether these drugs can be used to halt the death of overworked pancreatic cells in various experimental models of diabetes. We hope that someday soon our research will help lead to new and better drugs to treat patients suffering from type 2 diabetes.

SCIENTIFIC SUMMARY (Please also see http://papalab.ucsf.edu)

My UCSF lab’s scientific research aims to understand, at the molecular and cellular levels, how protein unfolding in the endoplasmic reticulum (ER) causes human disease. All eukaryotic cells use a fascinating intracellular signaling pathway called the unfolded protein response (UPR) to ensure that the machinery needed to fold secretory proteins is present in sufficient quantity to meet cellular needs. When the ER’s protein folding needs outweigh its capacity to sustain the folding process, cells experience a unique form of stress—“ER stress”— which triggers the UPR pathway. UPR outputs initially reduce ER stress through augmenting the amount of ER-resident chaperones and protein folding enzymatic activities. However, if ER stress cannot be alleviated through these adaptive outputs, the UPR switches strategies and instead triggers programmed cell death (apoptosis) of stressed cells.

ER stress-mediated apoptosis is now being widely linked to many important human diseases. ER stress-mediated diseases occur when specialized cells in the body that evolved to secrete proteins—“professional secretory cells”— die prematurely. For example, ER stress-mediated apoptosis is now thought to be a central feature of the common human disease type 2 diabetes. Type 2 diabetes is known to occur when about 50% of pancreatic islet beta cells (specialized cells in the pancreas that synthesize and secrete insulin) die, leading to insufficient insulin levels in the blood. We hypothesize that pancreatic islet beta cells may become overworked as they try to counter peripheral insulin resistance in states of obesity and overnutrition (high fat and high carbohydrate diets). Overwork of these cells may cause them to experience elevated ER stress chronically. In turn, elevated ER stress puts the beta cells at heightened risk for death as the UPR starts triggering apoptosis. As more beta cells die, the remaining beta cells experience greater and greater ER stress because they have to do more work per cell. This chain of events leads to a vicious cycle, as the disease sets in. The process of disease progression may take up to five years, providing us with a long time window to reduce, and possibly even to reverse, the course of the disease.

Our long term goals are to develop new drugs to reduce ER stress and cell death. It is conceivable that such drugs would be useful to treat diabetes. The questions we ask include: is there a “tipping point” of ER stress beyond which the UPR relegates beta cells to apoptosis? Can we intervene through pharmacology to adjust that tipping point, and reduce beta cell death. Our long-term goals are to answer these questions at the mechanistic level. Through such knowledge we may be able to discover UPR targets that can be drugged, and thereby develop novel approaches to treat many ER stress cell degenerative diseases such as type 2 diabetes.

To these ends, we have learned to actively manipulate the UPR pathway in living cells, via cell-permeable small molecules. Using chemical-genetics, we developed the first tools to wrest pharmacological control over the UPR (Science 302, 1533-1537 (2003)). Next, we were among the first to demonstrate, as proof-of-concept, that engagement of the UPR unfolded protein sensor IRE1, an ER-resident transmebrane protein with bifunctional kinase and RNase activities, with kinase inhibitors enhances cytoprotection in mammalian cells experiencing irremediable ER stress (Bioch Bioch Res Comm. 365 (2008) 777–783).

We also devised the first biosensors for measuring ER stress in single living cells, in real time, through employing redox-sensitive fluorescent protein sensors (Cell, 135(5):933-47 (2008)). We developed mathematical modeling to quantify and predict the benefit of UPR signaling (P.N.A.S 105(51):20280-5. (2008)). We have also recently elucidated the basis of life-death signaling through IRE1, showing that it has alternate RNAse outputs that are controlled by its kinase domain to promote divergent cell fates under ER stress (Cell, 138, 562–575 (2009)).

Through this work we identified several small molecule kinase inhibitors of IRE1 that can enforce its adaptive RNase outputs and in so doing tilt the cellular balance towards survival under ER stress.  We expect that these kinase inhibitory compounds will be powerful tools to investigate connections between ER stress, the UPR, and apoptosis of beta cells. Thus, we are currently advancing these tool compounds through medicinal chemistry efforts to make them more drug-like and useful for animal and pre-clinical studies.

We hope that our work may lead someday to the development of novel disease-modifying therapies for diabetes. Besides diabetes, however, such drugs may become generally useful to treat many other diseases proceeding from cell degeneration under unchecked ER stress. For example, several important neurodegenerative diseases, such as Alzheimer’s disease,Parkinson’s disease, and Lou Gehrig’s disease, are all now thought to result from protein unfolding and aggregation in different types of neurons. Hallmarks of high ER stress are apparent in the affected neuronal cells. It is therefore conceivable that small molecule drugs that reduce ER stress may be effective at modulating progression of these deadly neurodegenerative diseases as well.