Role of activated pancreatic stellate cells for severity, course, inflammation and organ function in mouse models of chronic pancreatitic

• Applicant: Dr. Georg Beyer
• Subject Area: Gastroenterology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 413708806

Chronic pancreatitis is a fibroinflammatory syndrom of the pancreas, during which repetitive inflammatory episodes cause fibrotic tissue remodeling with consecutive loss of endocrine and exocrine function as well as pain. The life-time risk for developing pancreas cancer is increased 16-45fold and patients with chronic pancreatitis have an increased risk of dying at a younger age compared to the non-affected population (3.6-5.0fold increased risk). Currently there is no causative treatment available. Pancreatic stellate cells (PSCs) are resident mesenchymal cells, which do get activated during repetitive or continueous inflammatory stimuli in chronic pancreatitis and redifferentiated towards a myofibroblast-like phenotype. Activated PSCs are characterized by abundant expression of aSMA (alpha smooth muscle actin), production of extracellular matrix proteins and contribute to the regulation of the local inflammatory infiltrate. Activation of PSCs depends on transforming growth factor-beta (TGFb)-signaling. If PSC-activation is a result of prolonged inflammation or contributes independently to the severity of chronic pancreatitis is not known and will be investigated in the proposed study. At first we will study, in which way the targeted depletion of aSMA-expressing PSCs in the transgenic aSMA-tk mous strain changes the course of chronic pancreatitis. In a second step we will investigate the therapeutic effects of PSC-overactivation by using a SMAD7-inhibitor, thus antagonizing the PSC-depletion. SMAD7 is a negative regulator of TGFb-signaling and it can be inhibited by GED-0301 (Mongersen) an antisense-desoxynukleotide. Because TGFb has pleitropic effects appart from PSC activation we will use cell-type-selective and antigen-specific aptamers bound to GED-0301 to facilitate uptake in PSCs, Macrophages and regulatory T-cells and study its effect on chronic pancreatitis. Chronic pancreatitis severity over a time course, quantification of fibrosis in correlation to severity, effect on the composition of the local inflammatory infiltrate and systemic inflammation as well as development of pain will serve as endpoints. We will use the pancreatic duct ligation model as the primary disease model as it resembles best the human phenotype. Repetitive cerulein injection model will be used for validation. The proposed experimental study will show, whether PSC-activation contributes to the course of chronic pancreatitis thus beeing a promising therapeutic target for the treatment of chronic pancreatitis.

• DFG Programme: Research Grants