Physiology and pathophysiology of human pancreatic acinar cells

人胰腺腺泡细胞的生理学和病理生理学

基本信息

批准号：
8434178
负责人：
ASHOK K SALUJA
金额：
$ 31.69万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8434178
关键词：
Acinar Cell Acinus organ component Admission activity Agonist Animal Model Animals Apoptosis Applications Grants Bile Acids Biliary Biology Caerulein Calcium Carbachol Caring Cholecystokinin Clinical Trials Coupling Cyclic AMP Cytoskeleton Data Development Diagnosis Disease Enzyme Precursors Enzymes Evaluation Event Exocrine pancreas Experimental Animal Model Experimental Models Functional disorder Future Grant Harvest Hospitals Human In Vitro Inflammatory Injury Islets of Langerhans Knowledge Lead Learning Lysosomes Modality Modeling Mus Necrosis Organ Outcome Pancreas Pancreas Transplantation Pancreatitis Pathogenesis Pathway interactions Patients Physiology Prevention Publishing Rattus Research Rodent Rodent Model Role Stimulus Tissue Donors Tissues Transplantation Trypsin Validation Vertebral column acute pancreatitis analog base cost experience human disease human tissue in vitro Model novel programs public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): Pancreatitis is an inflammatory disease of the pancreas. The U.S. alone sees over 300,000 hospital admissions for acute pancreatitis annually with costs exceeding $2B. However, there is currently no specific therapy for this disease, a lamentable situation arising from our incomplete understanding of its pathophysiology. In part, this situation can be ascribed to the fact that, due to the non-availability of human acinar tissue for experimentation, most of our current knowledge of the pathophysiology of pancreatitis arises from experimental animal models. However, our preliminary data as well as other published studies indicate that there are significant differences in the physiology and pathobiology of acinar cells between humans and rodents. Such information accentuates the urgent need to re-access data generated from rodent models in models which truly reflect human disease. This is further reinforced by the negative outcomes of the clinical trials using the information learnt from experimental animal models. Recently, the advent of endocrine pancreas transplantation programs has made healthy human exocrine pancreatic tissue from donor organs available for in vitro experiments. There are only a handful of such transplantation centers in the US, and to successfully harvest and study human acini in-vitro requires an experienced exocrine pancreas lab. At our center we are uniquely poised to fulfill both pre-requisites. In the current proposal, we intend to utilize acinar cells harvested from pancreata of healthy donors to study and validate basic tenets in the physiology and pathophysiology of human exocrine pancreas. The studies proposed in the current grant will first confirm the tenets of stimulus secretion coupling in human acinar cells, since these principles form the backbone of studies on pathophysiology of pancreatitis. Next, the pathophysiology of early acute pancreatitis will be studied in two different in vitro models of acute pancreatitis in human acinar cells: hyperstimulation model and the more clinically apt model of biliary pancreatitis. We believe that the data generated through the experiments proposed in the current grant proposal will form the basis, in the future, of directed research applicable to the pathophysiology of acute pancreatitis in humans and lead to accelerated development of specific therapy for its prevention and treatment.

描述（由申请人提供）：胰腺炎是胰腺的炎症性疾病。仅美国就会看到每年有300,000多个急性胰腺炎的住院，费用超过2B美元。但是，目前尚无针对这种疾病的特定疗法，这是由于我们对其病理生理学的不完全理解而引起的可悲情况。在某种程度上，这种情况可以归因于以下事实：由于人类腺泡组织进行实验，我们目前对胰腺炎病理生理学的大多数知识源于实验动物模型。但是，我们的初步数据以及其他已发表的研究表明，人类和啮齿动物之间腺泡细胞的生理学和病理学存在显着差异。这些信息强调了真正反映人类疾病的模型中从啮齿动物模型中产生的迫切需要。使用从实验动物模型中学到的信息的临床试验的负面结果进一步加强了这一点。最近，内分泌胰腺移植程序的出现使健康的人类外分泌胰腺组织来自可用于体外实验的供体器官。在美国，只有少数此类移植中心，并且成功地收获和研究人类的体外，需要经验丰富的外分泌胰腺实验室。在我们的中心，我们有独特的准备来实现这两个先决条件。在当前的提案中，我们打算利用从健康供体的胰腺收获的腺泡细胞来研究和验证人类外分泌胰腺的生理学和病理生理学中的基本原则。当前赠款中提出的研究将首先证实人腺泡细胞中刺激分泌耦合的宗旨，因为这些原理构成了胰腺炎病理生理学研究的主干。接下来，将在人类腺泡细胞中的两种不同的急性胰腺炎体外模型中研究早期急性胰腺炎的病理生理：过度刺激模型和更临床的胆汁胰腺炎模型。我们认为，当前赠款提案中提出的实验产生的数据将在将来构成适用于人类急性胰腺炎病理生理学的指示研究的基础，并导致加速对其预防和治疗的特定治疗。