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PRSS1 Mutation and Pancreatic Cancer Tumorigenesis

PRSS1 突变与胰腺癌肿瘤发生

基本信息

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
项目类别：
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

项目摘要

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.

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