Role of Notch Pathway in the Pathogenesis of Chronic Pancreatitis

Abstract public domain (NIH RePORTER)

Abstract Chronic pancreatitis (CP) is a fibro-inflammatory disorder of the pancreas which is histologically characterized by acinar cell loss, inflammation and fibrosis. Studies suggest that pancreatitis is also a risk factor for pancreatic cancer. Despite decades of research there is no specific therapy for CP. Recent studies point towards a central role of activated pancreatic stellate cells (PSCs) in the pathogenesis of CP-associated fibrogenesis. Activated PSCs have been shown to not only regulate the synthesis and degradation of extracellular matrix proteins but also modulate the immune system to a more pro-fibrogenic state. Elucidation of the pathways which drive the activation of PSCs will lead to the development of novel therapies. Notch signaling pathway, a highly conserved developmental pathway, has been shown to be upregulated in fibrotic diseases of liver4 and other organs. While activation of Notch pathway has been observed in human CP5, its role in pathogenesis of CP, and whether its inhibition can be used as a therapeutic strategy has not been explored. Our preliminary data curated from in-vitro and in-vivo studies suggest that - 1) Activated PSCs exhibit pro-fibrogenic characteristics in a Notch-pathway dependent fashion 2) Notch pathway is activated in multiple animal models of CP; 3) this activation is observed in the PSC and the acinar compartment; 4) PSC- specific deletion of Notch-signaling improves outcomes in CP, whereas acinar-specific Notch-pathway deletion has no role (neither improves nor worsens) in CP pathogenesis or recovery 5) Notch pathway inhibition with pharmacological inhibitors reduce CP severity. Based on these data, we hypothesize that “Notch pathway in PSCs is involved in the pathogenesis of chronic pancreatitis. Notch pathway in PSCs drives the pro- fibrogenic response and modulates the immune environment to a pro-fibrotic state.” The current proposal is focused towards evaluating the role of Notch pathway in the pathogenesis of CP as well as progression of recurrent acute pancreatitis (RAP) to CP. In specific aim 1, using mouse models with stellate cell specific Notch pathway knock-out or knock-in strategies as well as using in-vitro setup, we will evaluate the role of Notch pathway in PSCs in the pathogenesis of CP. In specific aim 2, we will elucidate the effect of Notch pathway in PSCs on the immune environment in CP. Finally, in specific aim 3 we will confirm the activation of Notch pathway in pancreatectomy specimen from patients with CP. Furthermore, the ability of clinically relevant pharmacologic inhibitors of Notch pathway to improve CP in mouse models as well as to prevent progression of recurrent acute pancreatitis (RAP) to CP will be evaluated. Successful execution of these studies will not only elucidate novel pathways involved in the pathogenesis of CP, but will also generate pre-clinical data for a future clinical trial of Notch pathway inhibition in the treatment of CP.

Public health relevance public domain (NIH RePORTER)

Project Narrative Despite decades of research, there is no specific treatment available for the treatment of chronic pancreatitis (CP), which is one of the known risk factors for development of pancreatic cancer. Based on our preliminary data, in the current proposal, we will study the role of Notch pathway in the pathogenesis of CP. Finally, we will also evaluate pharmacological inhibition of Notch signaling pathway as a novel therapeutic strategy against Chronic Pancreatitis.