The significance of trypsinogen degradation in protecting the pan

The significance of trypsinogen degradation in protecting the pancreas against pancreatitis is also underscored by the protective effect of the p.G191R anionic trypsinogen (PRSS2) variant, which undergoes trypsin-induced degradation.23 The physiological role of CTRC in promoting activation of proCPA1 and proCPA2

raises the possibility that loss of CTRC function increases pancreatitis risk through impaired check details carboxypeptidase activation.64 This model would predict that loss-of-function mutations in the CPA1 or CPA2 genes should be also risk factors for chronic pancreatitis. Surprisingly, this seems to be the case, as newer, yet unpublished studies indicate click here that CPA1 is a susceptibility gene for chronic pancreatitis, and loss of CPA1 function increases disease risk (Dr Heiko Witt, pers. comm., 2011). However, the mechanism through which reduced carboxypeptidase activity would promote pancreatitis development is not readily apparent yet. The p.A73T mutation increases the propensity of CTRC to elicit ER stress, possibly through mutation-induced misfolding.68 ER stress-induced apoptosis can accelerate the loss of functional acini and contribute

to exocrine insufficiency, a hallmark of chronic pancreatitis. These effects of the p.A73T mutant can be considered as gain of function, because the mutant CTRC protein triggers cellular signal transduction processes that result in acinar cell damage and increased risk of chronic pancreatitis. There are two caveats to this attractive model. First, more research is needed to clarify whether all

disease-associated CTRC mutants can elicit ER stress, or whether this is a unique property of the p.A73T mutant. Second, it remains unclear whether CTRC expression levels in the human pancreas Non-specific serine/threonine protein kinase are high enough for mutant CTRC proteins to induce ER stress. Nevertheless, ER stress emerges as a potentially new paradigm for the mechanism of genetic risk in chronic pancreatitis.70 The three mechanistic models described earlier reflect our current, rapidly-expanding understanding of CTRC function and mutational effects. The wealth of new information in this respect is a testimony to one of the fundamental benefits of human genetics: the stimulation of investigations into novel physiological functions and pathological pathways. The authors are grateful to Dr Jonas Rosendahl and Dr Sebastian Beer for critical reading of the manuscript. Studies in the senior author’s laboratory were supported by NIH grants R01 DK058088 and R01 DK082412 and ARRA grant R01 DK082412-S2. “
“Introduction: Currently empirical criteria are used to determine usability of donor livers however they have a low predictive value and alternative methods to determine viability are desirable.

Comments are closed.