Alcohol and the Exocrine Pancreas ER Stress Responses

酒精与外分泌胰腺 ER 应激反应

• 批准号: 7025120
• 负责人: STEPHEN J PANDOL
• 金额: $ 18.61万
• 依托单位: BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7025120
• 关键词: acinar cell; alcoholism /alcohol abuse; biological models; biological signal transduction; carbachol; cell death; cellular pathology; cholecystokinin; endoplasmic reticulum; epigenetics; gene expression; genetically modified animals; inflammation; laboratory mouse; laboratory rat; molecular chaperones; pancreas; pharmacology; protein folding; protein structure function; toxicology; transcription factor

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.

描述（由申请人提供）：急性和慢性胰腺炎发生在一些人谁滥用酒精。在这些疾病中，胰腺腺泡细胞是疾病发病机制的关键参与者。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，并通过凋亡和坏死进行细胞死亡。 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，并且在生理刺激后进一步增加。许多这些新生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中的遗传或表观遗传变化而不能适当折叠时，它们不能离开ER并引起"ER应激"或未折叠蛋白反应（UPR）。 UPR代表一组信号网络，其可以通过上调ER分子伴侣和折叠酶的表达以及降低蛋白质合成负荷来减弱ER应激。 根据我们初步研究中提出的与普遍定期审议有关的观察结果，我们提出了新的假设进行检验。这些包括酒精滥用可以通过引起新生蛋白质的表观遗传改变来启动胰腺腺泡细胞中的ER应激反应。 在酒精滥用的大多数情况下，UPR的保护成分（即ER分子伴侣和折叠酶的表达;以及mRNA翻译的抑制）占主导地位并防止细胞病理学。 然而，在其他情况下，UPR的保护成分被超过，导致病理反应（即炎症，细胞周期停滞和细胞死亡）。 本项目旨在进一步表征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，我们将直接测试UPR信号之一的保护作用，X-box结合蛋白1（XBP1）使用该信号基因缺失的动物。 该项目的结果将使我们能够进一步研究乙醇对UPR的影响与乙醇引起的胰腺炎病理反应的整合。