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Inflammatory diseases of the pancreas have no specific therapy. Discovery of the genetic basis of chronic pancreatitis identified the digestive enzyme trypsin as a therapeutic target. Preclinical testing of trypsin inhibition has been hampered by the lack of animal models. Here we report the T7D23A knock-in mouse, which carries a heterozygous p.D23A mutation in mouse cationic trypsinogen (isoform T7). This trypsinogen mutant autoactivates to trypsin 50-fold faster than wild type. T7D23A mice develop spontaneous acute pancreatitis with edema, necrosis and serum amylase elevation at an early age followed by progressive atrophic chronic pancreatitis with acinar cell loss, fibrosis, dilated ducts and adipose replacement. Markedly elevated trypsin activity is apparent at first signs of pancreatitis and persists into later stages of the disease. This remarkable model provides in vivo proof of concept that trypsinogen autoactivation can drive onset and progression of chronic pancreatitis and therapy should be directed against intra-pancreatic trypsin.
Pubmed ID: 30487519
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Commercial organism provider selling mice, rats and other model animals. American corporation specializing in a variety of pre-clinical and clinical laboratory services for the pharmaceutical, medical device and biotechnology industries. It also supplies assorted biomedical products and research and development outsourcing services for use in the pharmaceutical industry. (Wikipedia)
View all literature mentionsPrivately held company that develops and produces antibodies, ELISA kits, ChIP kits, proteomic kits, and other related reagents used to study cell signaling pathways that impact human health.
View all literature mentionsAmerican chemical, life science and biotechnology company owned by Merck KGaA. Merger of Sigma Chemical Company and Aldrich Chemical Company. Provides organic and inorganic chemicals, building blocks, reagents, advanced materials and stable isotopes for chemical synthesis, medicinal chemistry and materials science, antibiotics, buffers, carbohydrates, enzymes, forensic tools, hematology and histology, nucleotides, proteins, peptides, amino acids and their derivatives.
View all literature mentionslaboratory mouse with name C57BL/6N from MGI.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
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