PRSS1 Mutation and Pancreatic Cancer Tumorigenesis

PRSS1 突变与胰腺癌肿瘤发生

• 批准号: 10295559
• 负责人: Baoan Ji
• 金额: $ 43.84万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10295559
• 关键词: Acinar Cell; Age; Animal Model; Biochemical; Biological; Cancer Etiology; Cations; Cellular Stress; Cessation of life; Chronic; Cleaved cell; Development; Disease; EIF-2alpha; Environmental Risk Factor; Etiology; Event; Functional disorder; Gene Mutation; Genes; Goals; High Fat Diet; Human; In Vitro; Inflammation; Inflammatory; Intervention; Lead; Lesion; Life; Link; Malignant neoplasm of pancreas; Mediating; Modeling; Mus; Mutation; Nature; Obesity; Oncogenic; PAR-2 Receptor; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatitis; Pathogenesis; Pathway interactions; Patients; Penetrance; Pharmacology; Phenotype; Play; Preventive; Property; Proteinase-Activated Receptors; Recurrence; Regulation; Risk; Risk Factors; Role; SRC gene; Savings; Signal Pathway; Signal Transduction; Smoking; TP53 gene; Testing; Therapeutic Intervention; Transgenic Organisms; Trypsin; Trypsinogen; acute pancreatitis; chronic pancreatitis; chymotrypsin C; cigarette smoking; endoplasmic reticulum stress; extracellular; genetic approach; hereditary pancreatitis; high risk; human disease; human tissue; improved; in vivo; inflammatory milieu; insight; mouse model; mutant; novel; pancreas development; pancreatic ductal adenocarcinoma model; pancreatic tumorigenesis; premalignant; prevent; preventive intervention; protein expression; tool; transcription factor; transcription factor CHOP; tumorigenesis

Abstract: The 5-year relative survival of pancreatic ductal adenocarcinoma (PDA) patients is only 8%. PDA is predicted to be the second-leading cause of cancer related death in the U.S. by 2030. Understanding the key signaling mechanisms of tumorigenesis is critical for developing life-saving interventions. Hereditary pancreatitis (HP), an autosomal-dominant disorder with recurrent episodes of acute pancreatitis (AP) which eventually develops into chronic pancreatitis (CP), has a cumulative risk of pancreatic cancer of 44% by age 70 years. Cationic trypsinogen gene (or PRSS1) mutations are the most common causes of HP. Unfortunately, the development of targeted preventive or therapeutic interventions for HP has been hampered by gaps in our understanding of its pathophysiology, which is mainly due to the practical difficulties in obtaining tissues from human pancreas at early stages of the disease and the lack of animal models that recapitulate the human form of this disease. Recently we have developed a novel model of HP by expressing a common mutant of human PRSS1 (PRSS1R122H) in mice (J Clin Invest. 2020 Jan 2;130(1):189-202). Transgenic expression of mutant PRSS1 caused severe AP which progresses to CP, precancerous PanIN lesions, and pancreatic cancer. This model of HP will provide us with a powerful tool to fulfill our long-term goal of understanding the initiating events of HP and developing specific strategies to prevent its progression to pancreatic cancer. In this proposal, we will use our unique humanized pancreatitis model to test our central hypothesis that etiological factors and PRSS1 gene mutation cooperatively cause pancreatic tumorigenesis by intra-acinar cell stress signaling pathways and a trypsin receptor-mediated constant inflammatory milieu. We will characterize these signaling pathways in this newly developed HP model and investigate their roles in pancreatic cancer tumorigenesis by both pharmacological and genetic approaches. We expect these studies will significantly improve our understanding of the pathogenesis of HP, its progression to pancreatic cancer, and provide new insights for developing/testing novel preventive and therapeutic interventions.

摘要： 胰腺导管腺癌（PDA）患者的5年相对生存率仅为8%。PDA是 预计到2030年，它将成为美国癌症相关死亡的第二大原因。了解关键 肿瘤发生的信号机制对于制定拯救生命的干预措施至关重要。遗传性 胰腺炎（HP）是一种常染色体显性遗传疾病，伴有反复发作的急性胰腺炎（AP）， 最终发展为慢性胰腺炎（CP），按年龄计算，胰腺癌的累积风险为44 70年了阳离子胰蛋白酶原基因（或PRSS 1）突变是HP最常见的病因。不幸的是， 针对HP的有针对性的预防或治疗干预措施的发展一直受到我们 了解其病理生理学，这主要是由于在获得组织的实际困难， 人类胰腺在疾病的早期阶段和缺乏重演人类形式的动物模型 这种疾病的最近，我们通过表达人类HP的一种常见突变体， PRSS 1（PRSS 1 R122 H）在小鼠中的表达（J Clin Invest. 2020年1月2日;130（1）：189-202）。突变体的转基因表达 PRSS 1引起严重AP，其进展为CP、癌前PanIN病变和胰腺癌。这 HP的模型将为我们提供一个强大的工具，以实现我们的长期目标，了解启动 HP事件和制定具体的策略，以防止其发展为胰腺癌。在这 我们将使用我们独特的人源化胰腺炎模型来测试我们的中心假设，即病因学 PRSS 1基因突变与胰腺癌发生的相关性研究 信号通路和胰蛋白酶受体介导的恒定炎症环境。我们将描述这些 在这个新开发的HP模型中的信号通路，并研究它们在胰腺癌中的作用 通过药理学和遗传学方法来治疗肿瘤。我们预计这些研究将大大 提高我们对HP发病机制及其向胰腺癌发展的认识，并提供新的 对开发/测试新型预防和治疗干预措施的见解。