Regulation of pancreatitis severity

Va Connecticut Healthcare System, West Haven CT

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Abstract

? DESCRIPTION (provided by applicant): This proposal will examine a newly described secretory protein, renalase, which appears to have a novel protective effect in acute pancreatitis (AP). AP has an incidence of up to 5/10,000, can cause death in 30% of those with severe disease, and is the most common reason for hospitalization for individuals with gastrointestinal disease. Since the disease is often caused by alcohol abuse and increases in incidence with age, it is frequently encountered in our Veteran population. Moreover, the risks for both developing AP and for severe disease are increased in chronic renal failure (CRF). Since CRF is common in our aging population of Veterans, it represents another relevant risk factor. We propose to study renalase, a serum protein that is produced in the kidneys and other tissues, that disappears from the serum with renal disease and other acute injuries. Renalase appears to have a potent protective pro-survival effect in the kidneys. We hypothesize that renalase will also have a protective role in AP and that decreases in renalase (serum and tissue) during some forms of injury, including acute pancreatitis, will result in more severe disease. We will examine the hypothesis with the following Specific Aims: 1) Determine whether serum renalase levels correlate with the presence of pancreatitis and its severity by examining its levels in sera and tissues from murine models of AP and in sera from patients with acute pancreatitis and controls; 2) Examine the effects of genetic deletion, peptide inhibition, and CRF on the severity of experimental murine AP; 3) Investigate whether exogenous recombinant renalase reduces severity of experimental acute pancreatitis in murine models and in human pancreatic acinar cells; 4) Determine whether the protective effects of renalase on pancreatitis-associated acinar cell injury is mediated by renalase activation of the plasma-membrane Ca2+ ATPase (PMCA) and Ca2+- extrusion. Mild and severe models of murine AP will be examined. Our preliminary data show the following: i) Serum renalase levels significantly decrease more than 50% within 2 hrs. after the initiation of murine AP and in humans with AP; ii) Genetic deletion of renalase results in a more severe phenotype of murine AP than wild- type controls; iii) Administering recombinant renalase reduces pancreatitis injury in isolated acinar cells and decreases the severity of murine AP in vivo whether given before or after disease onset; iv) Renalase binds to an isoform of the PMCA (PMCA4b) and enhances Ca2+-efflux from the pancreatic acinar cell; iv) PMCA inhibition enhances injury of acinar cells in pancreatitis. Our preliminary data firmly supports our hypothesis and demonstrates that we have the unique tools needed to complete the planned studies. The proposed work has the potential to provide a biomarker for pancreatitis and, more importantly, to characterize an attractive therapeutic target.