Deciphering Mechanisms Promoting Inflammation and Impaired Pancreas Recovery in Chronic Pancreatitis
Abstract
This proposal addresses the Fiscal Year 2019 Peer Reviewed Medical Research Program (PRMRP) Topic Area of Pancreatitis and is an expansion of the PR140717P2 project entitled “Targeting Trypsin-Inflammation Axis for Pancreatitis Therapy in a Humanized Pancreatitis Model” that was awarded under the PRMRP, Investigator-Initiated Research Award, W81XWH-14-PRMRP-IIRA. The pancreas is an organ of our body that produces digestive enzymes to digest food and hormones that control the levels of sugar in blood. Pancreatitis, especially due to alcohol abuse or genetic mutations in digestive enzymes, is a progressive inflammatory disease of the pancreas with chronic forms causing significant patient suffering. Pancreatitis is a leading cause of hospitalizations for gastrointestinal disorders, and a significant source of morbidity, mortality, and reduced quality of life among sufferers. Pancreatitis causes symptoms of pain and frequently requires narcotics for pain control. Complications include pseudocysts, narrowing of the ducts carrying digestive enzymes, and difficulties to digest food or control blood glucose levels (termed exocrine and endocrine dysfunction, respectively). As a spectrum disease, an acute episode of pancreatitis often leads to recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP), both of which substantially increase the risk of pancreatic cancer. Currently there are no approved drugs that can alter the disease course or prevent progression to chronic inflammation, exocrine and endocrine dysfunction, or pancreatic cancer development. In addition to lack of treatments, diagnostic tests for the progressive and chronic forms of pancreatitis are lacking often leading to patients suffering with symptoms without a diagnosis to explain them. Although pancreatitis occurs in the general population, the incidence and prevalence are greater in the military and Veteran populations. For example, cumulative incidence of acute pancreatitis (AP) in the military population (2008-2012) was 1 per 1,000 patient years, compared to 0.6 per 1,000 patient years in the general population. Prevalent alcohol use and smoking, in particular, among Veterans is thought to be an underlying cause for high rates of pancreatitis. Our proposed studies will have immense both short-term and long-term impact on the major unmet needs in the pancreatitis continuum. Regarding therapeutics, the work we have done during the funding period of the past 3 years demonstrated that the mouse model we have developed with the genetic mutation in the digestive enzyme trypsinogen (PRSS1 p.R122H) sensitizes the pancreas to alcoholic and non-alcoholic pancreatitis. Furthermore, in this model the pancreas does not recover from pancreatitis, and the tissue progresses to the pathology of CP. There is no other preclinical model available that has the characteristics of lack of recovery and progression of pancreatitis to chronic forms with risk of cancer. Thus, this model provides an unprecedented opportunity to determine the pathologic pathways involved in the development of alcoholic CP. In fact, our preliminary data show great promise demonstrating that key factors released from the pancreatic cells in our model can initiate and propagate inflammation and pancreas scarring, the basic pathologic processes that occur in pancreatitis progressing to its chronic state. We plan experimental interventions with potential therapeutics that can be translated to clinical trials. Furthermore, the model and our stores of samples from human subjects with RAP and CP will allow us to cross-validate biomarkers of disease we observe in the animal models with those we find in the human samples. Through our participation in the United States Consortium on Chronic Pancreatitis, Diabetes and Pancreatic Cancer (CPDPC) and through one of its cohort studies, PROCEED, we will be able to initiate and carry out clinical trials to test the effects of agents we find
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010317
Entities
People
- Stephen J Pandol
Organizations
- Cedars-Sinai Medical Center
- United States Army