Targeting Trypsin-Inflammation Axis for Pancreatitis Therapy in a Humanized Pancreatitis Model
Abstract
Pancreatitis is an inflammatory disease of the pancreas that causes significant morbidity and mortality. Pancreatitis occurs in acute and chronic variants. Acute pancreatitis (AP) is the single most frequent gastrointestinal cause of hospital admissions and cost an estimated $2.6 billion per year. Chronic pancreatitis (CP) is also the strongest risk factor for pancreatic cancer -- the fourth leading cause of cancer related death in the United States. Of high relevance to this proposal is a recent study from the Veterans Health Care System showing that 10.7% of patients with a diagnosis of pancreatitis were found to have pancreatic cancer within a 2-year period after the pancreatitis diagnosis. Furthermore, the prevalence of alcohol drinking and smoking, risk factors of pancreatitis, is high in the Veteran population and military personnel. Unfortunately, there is no proven pharmacologic entity specifically for the treatment of pancreatitis. Most of our knowledge on pancreatitis is based on research conducted using experimental models. However, lack of clinically relevant models has significantly hampered the investigation of the mechanisms of pancreatitis pathogenesis and the development of effective preventive and therapeutic interventions. Recent findings that human and mouse trypsinogen, a key initiator of pancreatitis, bear distinct biochemical properties may provide the best explanation for the limitations of current models. Pancreatitis is an autodigestive disease. During the past two decades, researchers discovered that premature activation of trypsinogen in pancreatic acinar cells is a key initiator of this disease. This notion is strongly supported by the observation that gain-of-function trypsinogen mutations (e.g., PRSS1R122H) were associated with human hereditary pancreatitis (HP). Recent discovery indicated that human and mouse PRSS1 possess distinct biochemical property. Therefore, novel models with expression of human trypsinogen are required to elucidate the explicit role of intracellular trypsin in the pathogenesis of human pancreatitis. However, many attempts to develop the HP model have not been successful since the discovery of R122H mutation of PRSS1 gene is the cause of HP in 1996. As now we understand, there are two major obstacles for successful development of this model. One is that introduction of human PRSS1R122H equivalent mutations to mouse PRSS1 does not recapitulate the pathogenic biochemical phenotype observed in human PRSS1. The other obstacle is the low transgenic expression levels from the mostly commonly used short elastase gene promoter/enhancer. We overcame these problems and developed a transgenic mouse using the full-length human PRSS1 gene. Histologically, this model faithfully mimics human hereditary pancreatitis. To our knowledge, it is the first reliable model for this disease. Humans bearing the PRSS1R122H gene are not born with pancreatitis and the first episode of AP occurs at a mean age of 10, suggesting physiological/environmental modifying factors are needed for the development of the disease. Therefore, HP provides a prototype for studying the interaction between the genetic basis and environmental factors in pancreatitis. With this novel model, we will test our central hypothesis that physiological/environmental factors interact with mutant PRSS1 to activate the trypsin-ER stress-inflammation axis and cause both acute and chronic pancreatitis. Targeting the ER stress and inflammatory cascade will be beneficial for pancreatitis prevention and therapy. We will examine physiological factors (sex hormones) and environmental factors (alcohol and smoking) on the development of pancreatitis using both genetic and pharmacological approaches. We will also test reagents targeting the trypsin-inflammation pathways for pancreatitis prevention and therapy. We expect that this study will elucidate fundamental mechanisms of pancreatitis. These studies
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510257
Entities
People
- Baoan Ji
Organizations
- Mayo Clinic
- United States Army