Pancreatitis can be a devastating clinical condition associated with considerable morbidity and mortality that is believed to result from premature activation of pancreatic enzymes within the parenchyma of the gland, leading to tissue autodigestion, subsequent inflammation, and ultimately tissue destruction. It is apparent that a number of complex and interrelated processes involving activation of pancreatic enzymes and inflammatory mediators participate in a cascade of events that produce pancreatitis. However, the precise pathogenic steps producing the final manifestations of the disease are not established. Neurogenic inflammation is a well established principle in some inflammatory conditions where neurotransmitters such as substance P are key mediators of pain sensation, neutrophil infiltration, edema, and local proteolysis. Mice deficient in the neurokinin-1 (NK-1) receptor have been shown to have less severe experimental pancreatitis compared to normal mice suggesting that substance P is important for the full inflammatory response. Recent studies by the PI and others have linked substance P release from primary sensory neurons to pancreatic inflammation and pancreatitis and suggest that primary sensory neuronal activation is an important upstream event in the development of pancreatitis. Primary afferent neurons are capsaicin-sensitive and express the capsaicin receptor [known as the vanilloid receptor-1 (VR1)]. The PI's preliminary pharmacological data indicate that VR1 inhibition reduces the severity of experimental pancreatitis. The current application is designed to test the hypothesis that primary sensory innervation is a necessary component of acute and chronic pancreatitis. The goal of this project is to define the upstream events from NK-1 receptor activation that initiate pancreatitis. These studies will utilize recently developed mouse models to examine the following Specific Aims: (1) To establish the critical role of VR1 in pancreatic inflammation and pancreatitis by determining if VR1 knock-out mice are protected against acute and/or chronic pancreatitis; (2) To determine if intrapancreatic trypsin inhibition, through the pancreatic specific expression of PSTI-I in transgenic mice, protects against pancreatitis through a VR1-mediated mechanism; (3) To characterize the endogenous ligands for the VR1 receptor responsible for mediating the inflammatory response in pancreatitis. These results should help both elucidate the importance of primary sensory innervation in the pathogenesis of pancreatitis and provide possible new strategies for the treatment of pancreatitis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-GMA-3 (01))
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Serrano, Jose
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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Romac, Joelle M-J; Shahid, Rafiq A; Swain, Sandip M et al. (2018) Piezo1 is a mechanically activated ion channel and mediates pressure induced pancreatitis. Nat Commun 9:1715
Liddle, Rodger A (2017) Location, Location, Location . . . It Is Important in Pancreatitis, Too. Cell Mol Gastroenterol Hepatol 3:6-7
Kanju, Patrick; Chen, Yong; Lee, Whasil et al. (2016) Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain. Sci Rep 6:26894
Anderson, Michelle A; Akshintala, Venkata; Albers, Kathryn M et al. (2016) Mechanism, assessment and management of pain in chronic pancreatitis: Recommendations of a multidisciplinary study group. Pancreatology 16:83-94
Shahid, Rafiq A; Vigna, Steven R; Layne, Amanda C et al. (2015) Acinar Cell Production of Leukotriene B4 Contributes to Development of Neurogenic Pancreatitis in Mice. Cell Mol Gastroenterol Hepatol 1:75-86
Shahid, Rafiq A; Wang, David Q-H; Fee, Brian E et al. (2015) Endogenous elevation of plasma cholecystokinin does not prevent gallstones. Eur J Clin Invest 45:237-46
Bohórquez, Diego; Haque, Fariha; Medicetty, Satish et al. (2015) Correlative Confocal and 3D Electron Microscopy of a Specific Sensory Cell. J Vis Exp :e52918
Chandra, Rashmi; Liddle, Rodger A (2014) Recent advances in the regulation of pancreatic secretion. Curr Opin Gastroenterol 30:490-4
Vigna, Steven R; Shahid, Rafiq A; Liddle, Rodger A (2014) Ethanol contributes to neurogenic pancreatitis by activation of TRPV1. FASEB J 28:891-6
Chandra, Rashmi; Liddle, Rodger A (2013) Modulation of pancreatic exocrine and endocrine secretion. Curr Opin Gastroenterol 29:517-22

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