Interdisciplinary Initiatives Program Round 10 - 2020

Martha Cyert, Biology
Sohail Husain, Pediatrics (Gastroenterology)

The proposal addresses the major health problem of pancreatitis, which is an excruciatingly painful medical emergency caused by inflammation of the pancreas. The pancreas is a banana-shaped organ that is located behind the stomach and that functions to maintain normal blood sugar levels by producing insulin and to digest a meal by producing pancreatic digestive enzymes. However, the pancreas is also a sensitive organ that can become inflamed due to a variety of triggers. The most common reason for pancreatitis is the obstruction of gallstones at the outlet of the pancreatic duct, causing backup of pancreatic juice. In addition, there are a host of genetic causes. Many patients state that pancreatitis is the most painful affliction that they have ever suffered. Pancreatitis is also among the top reasons for hospitalization due to a gastrointestinal illness in the US and accounts for more than a quarter million visits per year. One in five patients with pancreatitis develop severe complications, requiring weeks of hospitalization and intensive care unit support, and one in five of these severely affected patients succumb to death. It is also sobering to know that, as physicians, in most cases we can only provide the same type of care that we have provided for over a century, which is pain control and supportive IV fluid therapy. The reason for the lack of specific interventions to prevent or treat pancreatitis is that the molecular pathways involved in the transduction of pancreatitis are not well known.

The Husain Lab recently made the discovery that signaling pathway involving a protein called calcineurin is critical for the development of pancreatitis. Calcineurin removes a phosphate from other proteins and is, therefore, called a phosphatase. This enzymatic action is an important method of conveying molecular signals to the cells and organs in which calcineurin is activated. We have published over half a dozen studies demonstrating that blocking  calcineurin blocks pancreatitis and that studying calcineurin pathways will lead to important therapeutics for pancreatitis. In these studies, we have used the prototypic inhibitors of calcineurin that are currently used in patients to suppress the immune system, for example, after organ transplantation. However, the problem is that the calcineurin inhibitor drugs target the many diverse functions of calcineurin throughout the body and could affect more than the intended treatment of pancreatitis.

The Cyert Lab has pursued fundamental investigations of calcineurin that reveal how this phosphatase acts only on a discrete subset of human proteins and have developed tools for systematically identifying proteins that calcineurin regulates throughout the body, most of which have not been previously studied.

The major goal of the current proposal is to identify specific proteins that, when regulated by calcineurin, result in pancreatitis. We will use several innovative methods to systematically screen thousands of proteins to identify the relevant targets. The benefit of determining these targets is that, in the long run, they will help us develop more focused therapies for pancreatitis that target the relevant calcineurin pathways, without blocking the normal functions of calcineurin.

The proposal is a new, unique collaboration between (1) a physician-scientist at Stanford School of Medicine whose primary laboratory research goals are to tackle the problem of pancreatitis (Dr. Husain) and (2) an investigator in the Department of Biology at Stanford whose primary research interests are to uncover the calcineurin phosphatase targets in human health and disease (Dr. Cyert). The collaborative effort will be clearly stronger than the sum of two independent projects because the two investigators will work together, as described in the proposal, to interrogate the calcineurin phosphatase targets in pancreatitis using their complementary expertise in applying cutting-edge biochemical and computational techniques to experimental pancreatitis and definitively identifying those targets. Overall, we believe the proposal to map out the calcineurin targets that are relevant to pancreatitis will be crucial to devising new therapies for a debilitating disease. We believe that our combined expertise is ideal to accomplish the task. Finally, the work will lead us to apply for larger funding through the National Institutes of Health (NIH), and specifically a branch of the NIH called the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), to further this medically important line of work.