Deciphering Pancreatitis Microenvironment through Intravital Imaging

PROJECT SUMMARY Acute pancreatitis (AP) is a prevalent gastrointestinal condition that leads to a significant number of hospitalizations and high healthcare costs. With no effective therapy currently available, there is an urgent need for research to develop successful treatments. This proposal aims to investigate the roles of trypsin and coagulation in the development of acute pancreatitis and explore the hypothesis that thrombin plays a crucial role in the disease. Previous studies have shown that thrombin, a dual thrombin and trypsin inhibitor, has superior effects in preventing and treating acute pancreatitis compared to selective trypsin inhibitors. This suggests that anti- trypsin and anti-coagulation mechanisms work together to combat the disease. To investigate this further, genetic approaches will be used, including a newly engineered trypsin knockout mouse model (T2457) and a conditional thrombin knockout mouse model. The research will focus on dissecting the roles of trypsin and coagulation in acute pancreatitis initiation and progression. Additionally, the impact of thrombin on the pancreatic microenvironment will be examined using a multi-photon intravital imaging system. Thrombin inhibitors, PAR receptor inhibitors, and PAR1 knockout mice will be utilized to gain a better understanding of the coagulation pathway's influence on acute pancreatitis. In the final aim, the project will concentrate on enhancing drug delivery to the inflamed pancreas, addressing the issue of low drug concentrations in the affected tissue. Dabigatran will be used as a model drug, and proof-of-principle studies will be conducted to develop pancreatitis-specific drugs that improve drug delivery. An intravenous formulation of dabigatran will be formulated and tested for therapeutic efficacy, along with two prodrugs designed to activate locally in the pancreas. The completion of this project will significantly advance the understanding of acute pancreatitis pathophysiology and contribute to the development of targeted therapies. The knowledge gained will provide a solid foundation for future clinical trials aimed at preventing and treating acute pancreatitis. Ultimately, this research has the potential to impact patient outcomes and improve the management of this challenging condition.