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Pathophysiology of Chronic Pancreatitis Associated with Misfolded PNLIP Risk Variants

与错误折叠的 PNLIP 风险变异相关的慢性胰腺炎的病理生理学

基本信息

批准号：
10444623
负责人：
Xunjun Xiao
金额：
$ 46.29万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444623
关键词：
Acinar Cell Age Animal Model Animals Apoptotic Atrophic Automobile Driving Biological Biological Assay Cell Culture Techniques Cell Death Cells Chinese Complex Data Development Disease Disease Progression Enzymes Ethanol Event Exhibits Fibrosis Functional disorder Genes Genetic Predisposition to Disease Goals Human In Vitro Induced Mutation Infiltration Inflammation Inflammatory Knowledge Lipase Measures Mediating Methods Modeling Mus Necrosis Onset of illness Pancreas Pancreatic Injury Pancreatic enzyme Pancreatitis Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Peptide Hydrolases Phenotype Pre-Clinical Model Predisposition Prevalence Process Protein Isoforms Proteins Recurrence Research Reticulum Risk Risk Factors Role Signal Pathway Signal Transduction Stress Testing Therapeutic Trypsin Trypsinogen Variant Western Blotting acute pancreatitis age related chronic pancreatitis early onset end stage disease endoplasm feeding gain of function genetic risk factor human model inhibitor insight interest misfolded protein mouse model mutant novel novel therapeutic intervention pre-clinical prevent protein degradation protein misfolding proteostasis proteotoxicity response risk variant stem targeted treatment therapeutic target therapy development transcriptome sequencing variant of unknown significance

项目摘要

PROJECT SUMMARY The primary goal of this application is to determine the mechanisms by which pancreatic triglyceride lipase (PNLIP) variants increase the risk for chronic pancreatitis (CP) in humans. Proteotoxicity caused by misfolded mutant digestive enzymes has been recognized as a novel trypsin-independent mechanism for CP, referred to as misfolding CP. Recent studies indicate that the development of CP is often a process of discrete recurrent acute pancreatitis (RAP) driven by genetic risk factors. Restoring proteostasis in the presence of misfolded proteins is an attractive therapeutic strategy to stop RAP and prevent progression to end-stage disease in misfolding CP patients. Critical knowledge gaps remain in understanding how misfolded proteins contribute to pancreatitis onset and progression primarily stemming from the paucity of animal models that recapitulate misfolding CP in humans. We have developed a pre-clinical model of human PNLIP T221M disease. PNLIP has no known role in trypsinogen activation or trypsin inactivation. In vitro, PNLIP T221M misfolds and causes proteotoxicty by triggering unmitigated ER stress. Our preliminary data show that Pnlip T221M mice exhibit progressive pancreatic acinar atrophy, inflammatory cell infiltration, fibrosis, and apoptotic and necrotic cell death; the pathological changes occur as early as at 1 month and become severe at 3-4 month. Our working hypothesis is that proteins encoded by risk variants of PNLIP cause CP by gain-of-function proteotoxicity through protein misfolding. To test this hypothesis, first we will systematically characterize Pnlip T221 mice including CP-like phenotypes, secondary complications, and the susceptibility to pancreatic injury when being challenged with ethanol feeding. Second, we will methodically investigate early biological responses triggered by pancreatic expression of pathogenic PNLIP T221M in mice to uncover potential novel targets to halt or prevent disease onset and progression. Third, we will assess the prevalence of protein misfolding and proteotoxicity underlies the disease mechanism of PNLIP variants of uncertain significance (VUS) found in CP patients using cell cultures and another mouse model of Pnlip F300L. Completion of these studies will establish mutation-induced misfolding of digestive enzymes as a relevant disease mechanism in the pathogenesis of CP and will identify potential therapeutic targets to stop RAP and prevent CP.

项目总结