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

• 批准号: 8228049
• 负责人: ASHOK K SALUJA
• 金额: $ 32.84万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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/8228049
• 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

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. PUBLIC HEALTH RELEVANCE: Pancreatitis is an inflammatory disease. Every year in the U.S. alone, more than 300,000 patients are diagnosed with pancreatitis and over two billion dollars are spent on their care. There is currently no specific therapy for these patients, a lamentable situation arising from our incomplete understanding of its pathophysiology. Due to the paucity of the availability of human pancreatic tissues for experimentation, most of our information about biology and pathobiology of the pancreatic acinar cells comes from studies in rodents. However, numerous studies have suggested that there are significant differences in the physiology of human and rodent acini. Studies pertaining to human pancreatic acinar cells have been hampered due to a lack of access to healthy human tissue. Recently, however, 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. Once completed, the data generated from the proposed studies will lead to accelerated development of specific therapies against pancreatitis.

描述（由申请人提供）：胰腺炎是胰腺的一种炎症性疾病。仅美国每年就有超过 300,000 人因急性胰腺炎入院，费用超过 20 亿美元。然而，目前这种疾病还没有具体的治疗方法，由于我们对其病理生理学的了解不完全，这是一个令人遗憾的情况。在某种程度上，这种情况可以归因于这样一个事实：由于无法获得用于实验的人体腺泡组织，我们目前对胰腺炎病理生理学的大部分了解都来自实验动物模型。然而，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的腺泡细胞的生理学和病理学存在显着差异。这些信息凸显了迫切需要在真正反映人类疾病的模型中重新访问啮齿动物模型生成的数据。使用从实验动物模型中学到的信息进行的临床试验的负面结果进一步强化了这一点。最近，内分泌胰腺移植计划的出现使得来自供体器官的健康人外分泌胰腺组织可用于体外实验。美国只有少数这样的移植中心，要在体外成功收获和研究人类腺泡，需要经验丰富的外分泌胰腺实验室。在我们的中心，我们有独特的能力来满足这两个先决条件。在当前的提案中，我们打算利用从健康捐赠者的胰腺中采集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的基本原理。当前资助中提出的研究将首先确认人类腺泡细胞中刺激分泌耦合的原理，因为这些原理构成了胰腺炎病理生理学研究的支柱。接下来，将在两种不同的人腺泡细胞急性胰腺炎体外模型中研究早期急性胰腺炎的病理生理学：过度刺激模型和更临床适用的胆源性胰腺炎模型。我们相信，通过当前拨款提案中提出的实验产生的数据将构成未来适用于人类急性胰腺炎病理生理学的定向研究的基础，并导致加速开发预防和治疗该疾病的特异性疗法。 公共卫生相关性：胰腺炎是一种炎症性疾病。仅在美国，每年就有超过 300,000 名患者被诊断患有胰腺炎，治疗费用超过 20 亿美元。目前还没有针对这些患者的具体治疗方法，这是由于我们对其病理生理学的不完全了解而造成的令人遗憾的情况。由于用于实验的人类胰腺组织很少，我们关于胰腺腺泡细胞生物学和病理学的大部分信息都来自啮齿类动物的研究。然而，大量研究表明，人类和啮齿动物腺泡的生理学存在显着差异。由于无法获得健康的人体组织，有关人类胰腺腺泡细胞的研究受到了阻碍。然而，最近内分泌胰腺移植计划的出现使得来自供体器官的健康人外分泌胰腺组织可用于体外实验。美国只有少数这样的移植中心，要在体外成功收获和研究人类腺泡，需要经验丰富的外分泌胰腺实验室。在我们的中心，我们有独特的能力来满足这两个先决条件。在当前的提案中，我们打算利用从健康捐赠者的胰腺中采集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的基本原理。一旦完成，拟议研究产生的数据将加速针对胰腺炎的特异性疗法的开发。