Targeting protein kinase D in alcoholic pancreatitis

靶向蛋白激酶 D 在酒精性胰腺炎中的作用

• 批准号: 9333159
• 负责人: STEPHEN J PANDOL
• 金额: $ 39.38万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333159
• 关键词: Acinar Cell; Address; Alcohol abuse; Alcoholic Pancreatitis; Alcohols; Animal Model; Animals; Apoptosis; Attenuated; BCL2 gene; Cell Death; Cell Death Signaling Process; Cell physiology; Cells; Cessation of life; Development; Disease; Down-Regulation; Enzyme Activation; Ethanol; Experimental Models; Family; Family member; G-Protein-Coupled Receptors; Genes; Genetic; Golgi Apparatus; Human; Inflammation; Inflammation Process; Inflammatory; Laboratories; Link; Mediating; Medical; Mitochondria; Modeling; Molecular; Mus; Necrosis; Pancreas; Pancreatitis; Pathogenesis; Pathologic; Pathway interactions; Patients; Permeability; Pharmacology; Phospholipase C; Phosphotransferases; Play; Process; Protein Isoforms; Protein Secretion; Protein-Serine-Threonine Kinases; Rattus; Regulation; Reporting; Rodent; Rodent Model; Role; Second Messenger Systems; Severities; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Testing; Therapeutic; Trypsinogen; Work; acute pancreatitis; alcohol effect; attenuation; cell type; chronic pancreatitis; cytochrome c; design; feeding; inhibitor-of-apoptosis protein; inhibitor/antagonist; knockout animal; loss of function; mouse model; new therapeutic target; novel; pre-clinical; protein kinase D; protein kinase inhibitor; response; small molecule; small molecule inhibitor; transcription factor; treatment strategy

Project Summary/Abstract Alcohol abuse is a major cause of pancreatitis. Despite numerous studies, the mechanisms of ethanol effects in pancreatitis remain poorly understood and no current therapies directed to the molecular pathogenesis of this serious medical disorder are available. Our previous work demonstrated that ethanol-sensitized inflammatory and cell death responses are key steps for the development of pathologic responses in both acute and chronic pancreatitis. We further showed that ethanol augments the activation of the pro-inflammatory transcription factors and necrosis death pathways in pancreatic acinar cells. However the mechanisms or signal transduction pathways mediating the modulatory effects of ethanol on inflammatory and cell death pathways have not been completely revealed. PKD/PKD1, PKD2, and PKD3, comprising a family of novel serine/ threonine protein kinase D, have recently emerged as important components in the signaling pathways initiated and transduced through G protein coupled receptors, phospholipase C, second messengers, and PKC-dependent and –independent mechanisms in a variety of cell types including pancreatic acinar cells. PKD is increasingly implicated in the regulation of multiple cellular functions. Of significant importance for pancreatitis, our studies demonstrated that PKD signaling is required for key pathological features of rodent experimental pancreatitis including NF-κB activation, acinar cell necrosis and inappropriate intracellular digestive enzyme activation. The necessary role of PKD in pancreatitis has been further confirmed with our recently developed mouse model of pancreas specific deletion of PKD isoform. In our preliminary studies with a rodent model of ethanol-induced pancreatitis, we found that ethanol feeding promoted PKD expression and enhances cerulein-induced PKD activation that was closely linked to ethanol-sensitized NF-κB activation and cell necrosis. These results indicate that ethanol sensitizes pancreatitis responses through mechanisms involving PKD. Thus, we hypothesize that PKD is potentially a novel therapeutic target in alcoholic pancreatitis. Potent and specific PKD inhibitors will have benefit in treating this disease by attenuating both the inflammatory and necrosis responses in this disease. To test this hypothesis, we will further determine the role of alcohol-induced effects on PKD in regulating key signals involved in inflammation and then determine the role of alcohol-induced effects on PKD in regulating cell death through non-mitochondrial and mitochondrial signal pathways. Both pharmacological and genetic loss-of-function approaches including selective deletion of the PKD gene in mice will be utilized to explore PKD functions. We will test currently available small molecule inhibitors of PKD and determine their therapeutic benefits in experimental models of alcoholic pancreatitis in animals and human pancreatic acinar cells.

项目总结/摘要 酒精滥用是胰腺炎的主要原因。尽管有许多研究，乙醇效应的机制 胰腺炎的发病机制仍然知之甚少，目前还没有针对这种疾病的分子发病机制的治疗方法。 有严重的医学疾病。我们以前的工作表明，乙醇致敏的炎症反应， 和细胞死亡反应是急性和慢性炎症中病理反应发展的关键步骤。 胰腺炎我们进一步表明，乙醇增强了促炎转录的激活， 胰腺腺泡细胞中的坏死因子和坏死死亡途径。然而， 调节乙醇对炎症和细胞死亡途径的调节作用的途径还没有被发现。 完全暴露。 PKD/PKD 1、PKD 2和PKD 3，包括新的丝氨酸/苏氨酸蛋白激酶D家族，具有 最近出现的重要组成部分的信号转导途径启动和通过G蛋白 偶联受体，磷脂酶C，第二信使，PKC依赖和非依赖机制， 包括胰腺腺泡细胞在内的多种细胞类型。PKD越来越多地参与调节 多种细胞功能。我们的研究表明，PKD对胰腺炎具有重要意义， 包括NF-κB在内的啮齿动物实验性胰腺炎关键病理特征需要信号传导 激活、腺泡细胞坏死和不适当的细胞内消化酶激活。的必要作用 胰腺炎中的PKD已经被我们最近开发的胰腺特异性 PKD同种型的缺失。在我们对酒精诱导的胰腺炎啮齿动物模型的初步研究中， 发现乙醇喂养促进PKD表达并增强蓝蛋白诱导的PKD活化， 与乙醇致敏的NF-κB活化和细胞坏死密切相关。这些结果表明，乙醇 通过涉及PKD的机制使胰腺炎反应敏感。因此，我们假设PKD是 可能是酒精性胰腺炎的新治疗靶点。有效和特异性PKD抑制剂将 通过减弱炎症和坏死反应， 疾病 为了验证这一假设，我们将进一步确定酒精诱导的PKD效应在调节PKD中的作用。 参与炎症的关键信号，然后确定酒精诱导的PKD效应在 通过非线粒体和线粒体信号通路调节细胞死亡。药理学和 包括选择性缺失小鼠PKD基因的遗传功能丧失方法将被用于 探索PKD功能。我们将测试目前可用的PKD小分子抑制剂，并确定其 在动物和人胰腺腺泡酒精性胰腺炎实验模型中的治疗益处 细胞