The pathologic processes that initiate and perpetuate acute pancreatitis remain unclear. A recognized feature of this disease is the accumulation of vacuoles in acinar cells. However, neither the identity of these vacuoles nor their role in the pathogenesis of pancreatitis are understood. We propose that excessive vacuole formation in pancreatitis is a consequence of a defect in autophagy and is directly linked to acinar cell death. Autophagy is an important adaptive process through which the cell degrades unneeded or defective cytoplasmic organelles. Organelles to be degraded are sequestered within double-membrane vacuoles called autophagosomes, which then fuse with lysososmes, forming autolysosomes. The material within autolysosomes is degraded by hydrolases such as cathepsins. An example of physiologic autophagy is that triggered by starvation. It proceeds via coordinated increases in autophagosomes and autolysosomes and stimulation of protein degradation necessary for the recycling of cellular components. On the other hand, defects in autophagy contribute to diseases. Lysosome associated membrane protein (LAMP)-1 and -2 are major components of lysosomal membrane. As shown in knockout mice, LAMP-2 is a critical mediator of lysosomal fusion with autophagosomes. Its deficiency leads to impaired autophagy and massive accumulation of autophagic vacuoles, especially in the heart and exocrine pancreas. LAMPs are glycoproteins, and they become unstable and rapidly degraded if underglycosylated. We hypothesized that excessive vacuolization in acute pancreatitis results from impaired autophagy, due to decreased LAMP levels caused by their defective glycosylation. In turn, the impaired autophagy leads to acinar cell death. Thus, our hypothesis proposes a mechanism for acinar cell vacuolization and further, links together the two major pathologic responses of pancreatitis, vacuolization and cell death.
Specific aims are:1). Characterize autophagy impairment in cerulein and CDE models of pancreatitis;in vitro, in CCK- hyperstimulated acinar cells;and in tissue from patients with acute pancreatitis. 2). Determine the effect of pancreatitis on glycosylation and stability of LAMP-1 and -2. 3). Determine the role of LAMP-2 in autophagy impairment in pancreatitis. 4). Determine the role of LAMP-2 in pathologic responses of pancreatitis. 5). Determine the interrelationship between autophagy impairment and death responses in pancreatitis. Public Health Relevance: Acute pancreatitis is a serious disease of exocrine pancreas, the pathobilogy of which remains unknown, and specific treatments for which do not exist. A recognized feature of this disease is the accumulation of vacuoles in exocrine pancreatic cells;however, their role in pancreatitis is not understood. Our hypothesis proposes a mechanism for this pathological process and, further, links it to pancreatic cell death.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
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Serrano, Jose
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
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Gukovskaya, Anna S; Gukovsky, Ilya; Alg├╝l, Hana et al. (2017) Autophagy, Inflammation, and Immune Dysfunction in the Pathogenesis of Pancreatitis. Gastroenterology 153:1212-1226
Gukovskaya, Anna S; Pandol, Stephen J; Gukovsky, Ilya (2016) New insights into the pathways initiating and driving pancreatitis. Curr Opin Gastroenterol :
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Gukovsky, Ilya; Gukovskaya, Anna S (2015) Impaired autophagy triggers chronic pancreatitis: lessons from pancreas-specific atg5 knockout mice. Gastroenterology 148:501-5
Mareninova, Olga A; Sendler, Matthias; Malla, Sudarshan Ravi et al. (2015) Lysosome associated membrane proteins maintain pancreatic acinar cell homeostasis: LAMP-2 deficient mice develop pancreatitis. Cell Mol Gastroenterol Hepatol 1:678-694
Gukovsky, Ilya; Li, Ning; Todoric, Jelena et al. (2013) Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer. Gastroenterology 144:1199-209.e4
Shalbueva, Natalia; Mareninova, Olga A; Gerloff, Andreas et al. (2013) Effects of oxidative alcohol metabolism on the mitochondrial permeability transition pore and necrosis in a mouse model of alcoholic pancreatitis. Gastroenterology 144:437-446.e6
Gukovsky, Ilya; Pandol, Stephen J; Mareninova, Olga A et al. (2012) Impaired autophagy and organellar dysfunction in pancreatitis. J Gastroenterol Hepatol 27 Suppl 2:27-32
Gukovskaya, Anna S; Gukovsky, Ilya (2012) Autophagy and pancreatitis. Am J Physiol Gastrointest Liver Physiol 303:G993-G1003
Gukovsky, Ilya; Pandol, Stephen J; Gukovskaya, Anna S (2011) Organellar dysfunction in the pathogenesis of pancreatitis. Antioxid Redox Signal 15:2699-710

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