Alcohol and the Exocrine Pancreas ER Stress Responses

描述(申请人提供)：急性和慢性胰腺炎发生在一些酗酒的人身上。在这些疾病中，胰腺腺泡细胞在疾病的发病机制中起着关键作用。我们实验室过去的工作表明，腺泡细胞产生促炎细胞因子和趋化因子，并通过凋亡和坏死经历细胞死亡。消化过程所需的腺泡细胞中的蛋白质合成水平是体内最高的之一，在生理刺激后进一步增加。许多新生的蛋白质在离开内质网(ER)之前必须经历折叠。 当蛋白质由于其结构的遗传或表观遗传变化而不能适当折叠时，它们就不能退出内质网而引起“内质网应激”或未折叠蛋白反应(UPR)。UPR代表了一组信号网络，可通过上调ER伴侣和折叠酶的表达来缓解内质网应激，并降低蛋白质合成负荷。基于我们在初步研究中提出的与普遍定期审议相关的观察结果，我们提出了新的假设以供检验。其中包括酒精滥用可以通过导致新生蛋白质的表观遗传学改变而在胰腺腺泡细胞中引发内质网应激反应。在酒精滥用的大多数情况下，UPR的保护性成分(即内质网伴侣和折叠酶的表达；以及抑制信使核糖核酸的翻译)占上风，并防止细胞病理。 然而，在其他情况下，UPR的保护性成分超过了保护成分，导致了病理反应(即炎症、细胞周期停滞和细胞死亡)。本项目旨在进一步研究酒精治疗和神经体液刺激对UPR信号网络的影响，并将这些影响与胰腺炎的病理信号反应(如炎症和细胞死亡)相关联。此外，我们还将利用基因缺失的动物直接测试UPR信号之一X-box结合蛋白1(XBP1)的保护作用。这个项目的结果将使我们能够继续进行进一步的项目，整合乙醇对UPR的影响，以应对由于酒精引起的胰腺炎的病理反应，以及提供。

DESCRIPTION (provided by applicant): Acute and chronic pancreatitis occurs in some people who abuse alcohol. In these disorders, the pancreatic acinar cell represents a key participant in the pathogenesis of the disease. Past work from our laboratory has shown that the acinar cell generates pro-inflammatory cytokines and chemokines and undergoes cell death through apoptosis and necrosis. The levels of protein synthesis in the acinar cell required for digestive processes are among the highest in the body and increase further after physiologic stimulation. Many of these nascent proteins must undergo folding before exiting the endoplasmic reticulum (ER). When the proteins do not fold appropriately because of genetic or epigenetic changes in their structures, they are not able to exit the ER and cause "ER stress" or unfolded protein response (UPR). The UPR represents a set of signaling networks that can attenuate the ER stress by upregulation of the expression of ER chaperones and folding enzymes as well as decrease the protein synthetic load. Based on the observations related to the UPR presented in our preliminary studies we present novel hypotheses for testing. These include the suggestion that alcohol abuse can initiate an ER stress response in the pancreatic acinar cell by causing epigenetic alterations in nascent proteins. In most cases of alcohol abuse the protective components of the UPR (i.e. expression of ER chaperones and folding enzymes; and repression of translation of mRNA) prevail and prevent cellular pathology. However, in other cases the protective components of the UPR are exceeded leading to pathologic responses (i.e. inflammation, cell cycle arrest and cell death). The present project is designed to further characterize the effects of both alcohol treatments and neurohumoral stimulation on the signaling networks of the UPR and correlate these effects with the pathologic signaling responses of pancreatitis such as inflammation and cell death. In addition, we will directly test the protective role one of the UPR signals, X-box binding protein 1 (XBP1) using animals with gene deletion for this signal. The results deriving from this project will allow us to pursue further projects on integrating the effects of ethanol on the UPR to the pathological responses of pancreatitis due to ethanol as well as provide.