Mechanisms of Hereditary Pancreatitis

遗传性胰腺炎的机制

基本信息

批准号：
10380576
负责人：
Baoan Ji
金额：
$ 35.21万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-12 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380576
关键词：
Acinar Cell Age Age-Years Alcohols Animal Model Apoptosis Apoptotic Biochemical Biological Cations Cell Death Cell Death Signaling Process Cells DNA Damage Development Disease Environmental Risk Factor Etiology Event Experimental Models Functional disorder Gene Mutation Genes Genetic Genetic Models Goals Hospitalization Human In Vitro Inflammation Inflammatory Inflammatory Response Intervention Lead Legal patent Malignant neoplasm of pancreas Mediating Modeling Mus Mutation NF-kappa B Nature Necrosis Pancreas Pancreatitis Pathogenesis Pathway interactions Patients Penetrance Pharmacology Phenotype Play Prevention therapy Process Production Property Recurrence Regulation Research Risk Role SRC gene Severities Signal Pathway Signal Transduction TP53 gene Testing Therapeutic Intervention Tissues Trypsin Trypsinogen United States acute pancreatitis cell injury chronic pancreatitis chymotrypsin C clinically relevant endoplasmic reticulum stress gain of function gastrointestinal genetic approach hereditary pancreatitis high risk human disease human model humanized mouse improved in vivo insight mouse model mutant novel premature prevent preventive intervention targeted treatment tool transcription factor

项目摘要

Abstract: Hereditary pancreatitis (HP) is an autosomal-dominant disorder with recurrent episodes of acute pancreatitis (AP) that eventually develops into chronic pancreatitis (CP). Cationic trypsinogen gene (or PRSS1) mutations are the most common causes of HP. Importantly, HP patients have an extremely high risk of developing pancreatic cancer than other forms of CP. 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 the pancreas during the early stages of the disease and the lack of animal models that recapitulate the human form of the disease. Recently we have developed a novel model of HP by expressing a common mutant of human PRSS1 (PRSS1R122H) in mice at a level equivalent to that found in human HP. This new model will provide us with a powerful tool to fulfill our long-term goal of understanding the initiating events of HP and developing specific strategies for its prevention and therapy. In this proposal, we will use our unique humanized pancreatitis model to test our central hypothesis that etiological factors interact with genetic changes to increase trypsin activity, which causes pancreatitis by cell-autonomous cell death signaling pathways and non-cell-autonomous inflammatory pathways. We will characterize these signaling pathways in the HP model and investigate their roles by both pharmacological and genetic approaches. We expect these studies will significantly improve our understanding of the specific role of intracellular human trypsinogen activation during the pathogenesis of HP and provide new insights for preventive and therapeutic interventions. Importantly, our novel clinically relevant model will provide a powerful tool for developing and testing such interventions.

抽象的：遗传性胰腺炎（HP）是一种常染色体主导障碍，复发性发作胰腺炎（AP）最终发展为慢性胰腺炎（CP）。阳离子胰蛋白酶原基因（或 PRSS1）突变是HP的最常见原因。重要的是，HP患者的高度很高与其他形式的CP相比，患胰腺癌的风险。不幸的是，有针对性的发展 HP的预防或治疗干预措施受到我们对其理解的差距的阻碍病理生理学，这主要是由于从胰腺获得组织的实际困难在疾病的早期阶段以及缺乏概括人类形式的动物模型疾病。最近，我们通过表达一个常见的突变体开发了一种新颖的HP模型小鼠的人PRSS1（PRSS1R122H）的水平等同于人类HP中的水平。这个新模型将为我们提供一个强大的工具，以实现我们理解的长期目标惠普并制定了预防和治疗的特定策略。在此提案中，我们将使用我们的独特的人源化胰腺炎模型，以检验我们的中心假设，即病因学因素与遗传变化以增加胰蛋白酶活性，这会导致细胞自主细胞死亡引起胰腺炎信号通路和非细胞自主炎症途径。我们将描述这些 HP模型中的信号通路，并通过药理学和遗传研究其作用方法。我们希望这些研究将大大提高我们对特定作用的理解在HP发病机理期间，细胞内人胰蛋白酶原激活，并为预防和治疗干预措施。重要的是，我们的新颖临床相关模型将提供用于开发和测试此类干预措施的强大工具。