Graduation Date

Spring 5-10-2025

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Cancer Research

First Advisor

Prakash Radhakrishnan

Abstract

The increasing global prevalence of pancreatitis, along with its potential to rapidly progress to severe forms and its strong association with pancreatic cancer, makes it essential to understand the mechanisms underlying its progression. Truncated mucin-type O-glycans Tn and STn antigens are linked to pancreatic cancer and have also been seen in premalignant lesions and human pancreatitis samples. However, their role in pancreatitis remains unclear. This study uses a cerulein-induced acute pancreatitis animal model to investigate the impact of shortened O-glycans on immune response, pancreatic inflammation, and metabolic changes.

The loss of the molecular chaperone Cosmc in the pancreas causes the expression of truncated O-glycans, which leads to sustained inflammation and delayed tissue repair in the pancreatitis mouse model. Cre CosmcKO mice showed prolonged acinar dedifferentiation, edema, and increased serum amylase compared to wild-type controls. Similarly, with an initial increase in proinflammatory CD86-expressing M1 macrophages and sustained levels of the M2 macrophage marker Ym1/2 on day 14, the pancreas of Cre CosmcKO mice showed enhanced macrophage infiltration, which can eventually result in continued acinar-to-ductal metaplasia and fibrosis. The phosphoproteome analysis of the pancreas samples showed higher levels of phosphorylated perilipin-1, which is associated with enhanced lipolysis and free fatty acids in the pancreas that can worsen the damage. These findings collectively demonstrate that by resulting in a sustained inflammatory and metabolic imbalance, aberrant O-glycosylation of proteins in the pancreas can delay pancreatic recovery after pancreatitis.

Comments

2025 Copyright, the authors

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Available for download on Saturday, April 17, 2027

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