权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Proteotoxicity in the Pathophysiology of Chronic Pancreatitis

慢性胰腺炎病理生理学中的蛋白质毒性

基本信息

批准号：
8838103
负责人：
MARK E. LOWE
金额：
$ 33.25万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8838103
关键词：
Acinar Cell Address Apoptosis Autophagocytosis Cell Death Cell Death Signaling Process Cells Chronic Disease Clinical Data Degradation Pathway Development Disease Economic Burden Enzymes Esters Failure Figs - dietary Functional disorder Goals Health Homeostasis Inflammation Inflammatory Inflammatory Response Injury Intervention Knowledge Lipase MAPK8 gene Measures Metabolic stress Minisatellite Repeats Modeling Molecular Mus Mutation Nature Pancreas Pancreatic Injury Pancreatitis Pathogenesis Pathway interactions Patients Predisposition Process Proline Proteins Recurrence Reporting Risk Role Signal Pathway Signal Transduction Stress Tandem Repeat Sequences Trypsin Trypsinogen Variant acute pancreatitis base biological adaptation to stress cell injury chronic pancreatitis disulfide bond effective therapy gain of function health economics improved in vivo insight mouse model multicatalytic endopeptidase complex mutant new therapeutic target novel novel therapeutics patient population prevent protein aggregate response stem therapy development

项目摘要

DESCRIPTION (provided by applicant): Pancreatitis is an inflammatory disease with significant health and economic burdens that lacks an established therapy to prevent recurrent episodes or progression to chronic disease. Our long-term goal is to develop therapies for these diseases. The absence of effective therapies stems in part from our limited understanding about the pathophysiology of pancreatitis. The prevailing trypsin-dependent model holds that intracellular trypsinogen activation and failure of protective mechanisms responsible for trypsin inactivation are central to pathogenesis. Despite great effort the role of trypsin in pancreatitis remains speculative and incompletely defined. Recent studies suggest another mechanism for disease in patients with mutations in exocrine proteins, disruption of normal protein homeostasis and activation of ER overload pathways. As a result, expression of the mutant proteins is toxic to acinar cells and increases the risk for pancreatitis. With this model, the approach to developing new therapeutics would differ significantly from approaches based on the trypsin-dependent model. Herein, we address the hypothesis that carboxyl ester lipase (CEL) mutants associated with chronic pancreatitis activate adaptive cell signaling pathways and cell death pathways, initiate an inflammatory response and increase susceptibility of cells to injury by metabolic stress. The CEL mutations occur in the region containing a variable number of proline-rich tandem repeats (VNTR). Our preliminary data show that the DEL variants accumulate within the cells as aggregates and activate adaptive cell signaling pathways. We propose the following Specific Aims: 1) Determine the cellular pathways for the disposal of insoluble aggregates of CEL VNTR variants; 2) Identify the adaptive cell signaling pathways activated by expression of CEL VNTR variants; 3) Confirm our ex vivo results in mouse models that express CEL VNTR variants in the pancreas. The knowledge gained by the proposed studies will improve the overall understanding of pancreatic injury and provide insight into potential pharmacological interventions directed at a new therapeutic target, protein homeostasis.

描述（由申请方提供）：胰腺炎是一种炎症性疾病，具有显著的健康和经济负担，缺乏预防复发或进展为慢性疾病的既定治疗。我们的长期目标是为这些疾病开发治疗方法。缺乏有效的治疗方法，部分原因是我们对胰腺炎的病理生理学了解有限。流行的胰蛋白酶依赖性模型认为，细胞内胰蛋白酶原激活和负责胰蛋白酶失活的保护机制的失败是发病机制的核心。尽管做了大量的努力，胰蛋白酶在胰腺炎中的作用仍然是推测性的，并且没有完全确定。最近的研究表明，外分泌蛋白突变、正常蛋白质稳态的破坏和ER过载途径的激活是患者疾病的另一种机制。因此，突变蛋白的表达对腺泡细胞是有毒的，并增加胰腺炎的风险。使用该模型，开发新疗法的方法将与基于胰蛋白酶依赖性模型的方法显著不同。在这里，我们解决的假设，羧基酯脂肪酶（CEL）突变体与慢性胰腺炎激活适应性细胞信号通路和细胞死亡途径，启动炎症反应，增加细胞对代谢应激损伤的敏感性。CEL突变发生在含有可变数量的富含脯氨酸的串联重复序列（VNTR）的区域。我们的初步数据表明，DEL变体在细胞内积累为聚集体并激活适应性细胞信号通路。我们提出了以下具体目的：1）确定用于处理CEL VNTR变体的不溶性聚集体的细胞途径; 2）鉴定通过表达CEL VNTR变体激活的适应性细胞信号传导途径; 3）确认我们在胰腺中表达CEL VNTR变体的小鼠模型中的离体结果。通过拟议的研究获得的知识将提高对胰腺损伤的整体理解，并提供针对新的治疗靶点蛋白质稳态的潜在药理学干预的见解。