Apoptosis and Necrosis in Pancreatitis

描述（由申请人提供）：急性胰腺炎的发病和持续的病理过程尚不清楚。这种疾病的一个公认的特征是腺泡细胞中液泡的积累。然而，这些空泡的身份及其在胰腺炎发病机制中的作用都不清楚。我们认为胰腺炎中过多的液泡形成是自噬缺陷的结果，并与腺泡细胞死亡直接相关。自噬是细胞降解不需要的或有缺陷的细胞器的重要适应性过程。待降解的细胞器被隔离在称为自噬体的双膜液泡中，然后与溶酶体融合，形成自溶酶体。自溶酶体内的物质被水解酶如组织蛋白酶降解。生理性自噬的一个例子是由饥饿引发的自噬。它通过自噬体和自溶体的协调增加以及刺激细胞成分循环所必需的蛋白质降解来进行。另一方面，自噬缺陷导致疾病。溶酶体相关膜蛋白(LAMP)-1和-2是溶酶体膜的主要成分。如在基因敲除小鼠中所示，LAMP-2是溶酶体与自噬体融合的关键介质。它的缺乏导致自噬受损和自噬空泡的大量积累，特别是在心脏和胰腺外分泌。lamp是糖蛋白，如果糖基化不足，它们会变得不稳定并迅速降解。我们假设急性胰腺炎的过度空泡是由自噬受损引起的，这是由于其糖基化缺陷导致的LAMP水平降低。反过来，自噬受损导致腺泡细胞死亡。因此，我们的假设提出了一种腺泡细胞空泡化的机制，并进一步将胰腺炎的两种主要病理反应空泡化和细胞死亡联系在一起。具体目标有：1)；胰腺炎核蛋白和CDE模型的自噬损伤特征体外，CCK-超刺激的腺泡细胞；也存在于急性胰腺炎患者的组织中。2）. 确定胰腺炎对LAMP-1和lamp -2糖基化和稳定性的影响。3）. 确定LAMP-2在胰腺炎自噬损伤中的作用。4)。确定LAMP-2在胰腺炎病理反应中的作用。5)。确定胰腺炎自噬损伤与死亡反应之间的相互关系。

DESCRIPTION (provided by applicant): 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.