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.

项目摘要/摘要 酗酒是胰腺炎的主要原因。尽管进行了许多研究，但乙醇作用的机制 在胰腺炎中，人们的理解仍然很少，目前没有针对这一点的分子发病机理 有严重的医学障碍。我们以前的工作表明乙醇敏感性炎症 细胞死亡反应是急性和慢性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 胰腺腺泡细胞中的因素和坏死死亡途径。但是机制或信号转导 介导乙醇对炎症和细胞死亡途径的调节作用的途径尚未 完全揭示。 PKD/ PKD1，PKD2和PKD3完成了新的丝氨酸/苏氨酸蛋白激酶D 最近出现在通过G蛋白引发和转移的信号通路中的重要组成部分 耦合受体，磷脂酶C，第二使者以及PKC依赖性和非依赖性机制 多种细胞类型，包括胰腺腺泡细胞。 PKD越来越涉及的调节 多个细胞函数。对于胰腺炎至关重要，我们的研究表明PKD 啮齿动物实验性胰腺炎（包括NF-κB）的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。必要的角色 我们最近开发的胰腺特异性小鼠模型进一步证实了胰腺炎的PKD PKD同工型的缺失。在我们的初步研究中，通过乙醇引起的胰腺炎的啮齿动物模型，我们 发现乙醇喂养促进了PKD表达并增强了Cerulein诱导的PKD激活 与对乙醇敏感的NF-κB激活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。那我们假设PKD是 可能是酒精性胰腺炎的新型热靶标。有效和特定的PKD抑制剂将 通过衰减炎症和坏死反应来治疗这种疾病有益 疾病。 为了检验这一假设，我们将进一步确定酒精诱导的对PKD的影响在调节中的作用 涉及炎症的关键信号，然后确定酒精诱导的对PKD的作用 通过非线粒体和线粒体信号途径调节细胞死亡。两者都是药物和 通用功能丧失方法包括将小鼠中PKD基因的选择性缺失用于 探索PKD功能。我们将测试当前可用的小分子抑制剂，并确定它们 在动物和人类胰腺肿瘤的酒精性胰腺炎实验模型中的治疗益处 细胞。