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Genetic mutations in pancreatic digestive enzymes may cause protein misfolding, endoplasmic reticulum (ER) stress and chronic pancreatitis. The  CPA1 N256K  mouse model carries the human p.N256K carboxypeptidase A1 (CPA1) mutation, a classic example of a pancreatitis-associated misfolding variant.  CPA1 N256K  mice develop spontaneous, progressive chronic pancreatitis with moderate acinar atrophy, acinar-to-ductal metaplasia, fibrosis, and macrophage infiltration. Upregulation of the ER-stress associated pro-apoptotic transcription factor  Ddit3/Chop  mRNA was observed in the pancreas of  CPA1 N256K  mice suggesting that acinar cell death might be mediated through this mechanism. Here, we crossed the  CPA1 N256K  strain with mice containing a global deletion of the  Ddit3/Chop  gene ( Ddit3-KO  mice) and evaluated the effect of DDIT3/CHOP deficiency on the course of chronic pancreatitis. Surprisingly,  CPA1 N256K  x  Ddit3-KO  mice developed chronic pancreatitis with a similar time course and features as the  CPA1 N256K  parent strain. In contrast,  Ddit3-KO  mice showed no pancreas pathology. The observations indicate that DDIT3/CHOP plays no significant role in the development of misfolding-induced chronic pancreatitis in  CPA1 N256K  mice and this transcription factor is not a viable target for therapeutic intervention in this disease.

Misfolding-induced chronic pancreatitis in CPA1 N256K mutant mice is unaffected by global deletion of Ddit3/Chop