Models of Type 1 and Type II Hereditary Pancreatitis

描述（申请人摘要）：急性和慢性胰腺炎仍然是主要的

DESCRIPTION (Applicant's Abstract): Acute and chronic pancreatitis remain major healthcare problems. The lack of effective preventive and therapeutic strategies in these disease states stems from a lack of understanding regarding disease pathogenesis. The investigator's group has identified mutations responsible for two delayed-onset, autosomal dominant inherited forms of acute and chronic pancreatitis. An RI 17H mutation in the human cationic trypsinogen gene links with type I hereditary pancreatitis (HP I). An N211 mutation in the same gene links with type II hereditary pancreatitis (HP II). Biochemical data from other groups when combined with the results of there preliminary studies support the hypothesis that the HP I mutation in cationic trypsin renders the molecule resistant to proteolytic digestion, the persistence of mutant trypsin activity resulting in the creation of a "milieu" sufficient for clinically-apparent acute pancreatitis. The alterations in protein biochemistry responsible for the HP II phenotype remain unclear. In an initial attempt to develop an animal model of HP I, the investigator generated transgenic mice containing a diet-inducible pancreatic acinar cell-specific promoter coupled to either wild-type or HP I mutant human cationic trypsinogen. Unfortunately, these mice fail to develop pancreatitis spontaneously, and all available antibodies to human cationic trypsin cross-react with an identically sized mouse trypsin. The investigator believes that enhanced expression of antibody epitope-tagged human cationic trypsinogens will provide him with the best opportunity to develop a successful animal model of hereditary pancreatitis. Toward this end, the investigator proposes (1) studies comparing the biochemical properties of affinity-purified recombinant wild-type, R117H, and N21I human cationic trypsinogen/trypsin (+ I- epitope tag) utilizing a validated in vitro assay system. By design, these studies will also further test the investigator's hypothesis with regard to HP I mutant trypsin, and discern the biochemical alterations induced by the HP II mutation. The investigator will then (2) characterize murine pancreata and acinar cells expressing varying levels of epitope-tagged wild-type, R117H, and N2 11 human cationic trypsinogen/trypsin. The development of these animal models, in combination with the experimental design, should provide him with important insights into the events underlying the delayed-onset and pathophysiology of HP I, HP II and non-hereditary forms of acute and chronic pancreatitis.