Characterization of Pancreatic Disease in a Novel Porcine Cystic Fibrosis Model

新型猪囊性纤维化模型中胰腺疾病的表征

基本信息

批准号：
7934538
负责人：
Aliye Uc
金额：
$ 37.5万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-20 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7934538
关键词：
Aborted Fetus Acinar Cell Age Alleles Alpha Cell Amylases Animal Model Animals Anions Atrophic Bicarbonates Carbonic Anhydrase II Caring Cell Culture Techniques Cells Characteristics Child Care Childhood Cholecystokinin Chymotrypsinogen Clinical Collection Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Development Dilatation - action Disease Disease Progression Duct (organ) structure Endocrine Enzymes Epithelial Cells Exocrine pancreas Exocrine pancreatic insufficiency Family suidae Fatty acid glycerol esters Fetus Fibrosis Functional disorder Future Gastroenterologist Gene Expression Genes Gland Goals Growth Histopathology Human IL8 gene In Vitro Infant Inflammation Inflammatory Injury Innovative Therapy Insulin Ion Transport Knockout Mice Left Lesion Light Lipase Liquid substance Lung diseases Malnutrition Measurement Measures Metaplasia Modeling Molecular Profiling Morphology Mucous body substance Neonatal Screening Nutritional Pancreas Pancreatic Diseases Pancreatic Injury Pancreatic enzyme Patients Pattern Physiological Plug-in Pregnancy Proteins Quality of life Regulator Genes Research Role Secretin Staging Sus scrofa Testing Time Trypsin Trypsinogen apical membrane children with cystic fibrosis chymotrypsin cystic fibrosis patients cytokine design improved functioning in utero in vivo light microscopy mouse model novel nutrition pancreatic juice public health relevance response therapy design

项目摘要

DESCRIPTION (provided by applicant): Pancreatic involvement is common and the injury progresses to pancreatic insufficiency (PI) in the majority of patients with cystic fibrosis (CF). Currently, there are no treatments to halt the progression of pancreatic disease in CF and the exact mechanisms leading to the destruction of pancreas are not well-understood. Two major obstacles until now have been inaccessibility of the pancreas in humans and lack of a suitable animal model. We produced pigs (Sus scrofa) with a targeted disruption of both cystic fibrosis transmembrane conductance regulator (CFTR) alleles. These animals had pancreatic lesions markedly similar to those found in humans with CF and their pancreas had an increased number of inflammatory cells and higher levels of a proinflammatory cytokine, IL-8. The goal of this project is to fully characterize the anatomical and physiological features of CFTR-/- pig pancreas and to utilize the data obtained from this model to shed light on the pathophysiology of pancreatic disease in humans with CF. We plan to reach our goal with the following Specific Aims: (1) determine the ontogeny of exocrine pancreatic lesions in CFTR-/- pigs; and (2) determine the role of CFTR in regulating exocrine pancreatic function in vivo and in vitro. The first aim will test the hypothesis that pancreatic disease in CF starts as acinar plugs in utero and progresses over time to acinar cell atrophy, duct dilatation, mucous cell metaplasia and fibrosis. The anatomical origins, disease progression and pathophysiological features of the novel porcine model of CF will be characterized using histopathology, enzyme expression, pancreatic cell markers and microarray gene profiling. The impact of inflammation on the development and progression of the pancreatic lesions will be explored. The second aim will test the hypothesis that CFTR is directly involved in pancreatic Cl- and HCO3- secretion. The role of CFTR in regulating the exocrine pancreatic function of pigs will be determined in vivo (analysis of fecal fat and chymotrypsin; collection of pancreatic fluid) and in vitro (primary porcine ductular epithelial cell cultures) using CFTR-/- and CFTR+/+ pigs. The objective of this application is to study the pancreatic pathophysiology in our novel swine model of CF and to better understand the pathophysiological mechanisms leading to pancreatic involvement in CF. Our long-term goal is to design innovative therapies to preserve pancreatic function and improve the quality of life, growth delay and malnutrition in CF. PUBLIC HEALTH RELEVANCE: Pancreatic involvement is common and the injury progresses to pancreatic insufficiency (PI) in the majority of patients with cystic fibrosis (CF). Currently, there are no treatments to halt the progression of pancreatic disease in CF and the exact mechanisms leading to the destruction of pancreas are not well-understood. The goal of this application is to fully characterize pancreatic involvement in our novel CF pig model and to better understand the pathophysiological mechanisms leading to PI in CF.

描述（由申请人提供）：在大多数囊性纤维化 (CF) 患者中，胰腺受累很常见，并且损伤会进展为胰腺功能不全 (PI)。目前，尚无治疗方法可以阻止 CF 中胰腺疾病的进展，并且导致胰腺破坏的确切机制尚不清楚。迄今为止的两个主要障碍是人类胰腺难以接近和缺乏合适的动物模型。我们培育出的猪（Sus scrofa）对囊性纤维化跨膜电导调节因子（CFTR）等位基因进行了有针对性的破坏。这些动物的胰腺病变与人类 CF 患者的胰腺病变明显相似，并且它们的胰腺炎症细胞数量增加，促炎细胞因子 IL-8 水平较高。该项目的目标是充分表征 CFTR-/- 猪胰腺的解剖学和生理学特征，并利用从该模型获得的数据来阐明 CF 人类胰腺疾病的病理生理学。我们计划通过以下具体目标来实现我们的目标：（1）确定CFTR-/-猪外分泌胰腺病变的个体发育； (2)确定CFTR在体内和体外调节外分泌胰腺功能的作用。第一个目标将检验以下假设：CF 中的胰腺疾病始于子宫内的腺泡堵塞，并随着时间的推移进展为腺泡细胞萎缩、导管扩张、粘液细胞化生和纤维化。将使用组织病理学、酶表达、胰腺细胞标记和微阵列基因分析来表征新型猪 CF 模型的解剖起源、疾病进展和病理生理学特征。将探讨炎症对胰腺病变发生和进展的影响。第二个目标将检验 CFTR 直接参与胰腺 Cl- 和 HCO3- 分泌的假设。 CFTR 在调节猪外分泌胰腺功能中的作用将使用 CFTR-/- 和 CFTR+/+ 在体内（分析粪便脂肪和胰凝乳蛋白酶；收集胰液）和体外（原代猪导管上皮细胞培养物）进行确定猪。本申请的目的是研究我们新型 CF 猪模型中的胰腺病理生理学，并更好地了解导致 CF 胰腺受累的病理生理机制。我们的长期目标是设计创新疗法，以保护胰腺功能并改善 CF 患者的生活质量、生长延迟和营养不良。公众健康相关性：在大多数囊性纤维化 (CF) 患者中，胰腺受累很常见，并且损伤会进展为胰腺功能不全 (PI)。目前，尚无治疗方法可以阻止 CF 中胰腺疾病的进展，并且导致胰腺破坏的确切机制尚不清楚。本应用的目的是充分表征我们新型 CF 猪模型中胰腺受累的特征，并更好地了解导致 CF 中 PI 的病理生理机制。