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:
- 金额:$ 37.5万
- 依托单位:
- 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:
- 关键词:Aborted FetusAcinar CellAgeAllelesAlpha CellAmylasesAnimal ModelAnimalsAnionsAtrophicBicarbonatesCarbonic Anhydrase IICaringCell Culture TechniquesCellsCharacteristicsChild CareChildhoodCholecystokininChymotrypsinogenClinicalCollectionCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDataDevelopmentDilatation - actionDiseaseDisease ProgressionDuct (organ) structureEndocrineEnzymesEpithelial CellsExocrine pancreasExocrine pancreatic insufficiencyFamily suidaeFatty acid glycerol estersFetusFibrosisFunctional disorderFutureGastroenterologistGene ExpressionGenesGlandGoalsGrowthHistopathologyHumanIL8 geneIn VitroInfantInflammationInflammatoryInjuryInnovative TherapyInsulinIon TransportKnockout MiceLeftLesionLightLipaseLiquid substanceLung diseasesMalnutritionMeasurementMeasuresMetaplasiaModelingMolecular ProfilingMorphologyMucous body substanceNeonatal ScreeningNutritionalPancreasPancreatic DiseasesPancreatic InjuryPancreatic enzymePatientsPatternPhysiologicalPlug-inPregnancyProteinsQuality of lifeRegulator GenesResearchRoleSecretinStagingSus scrofaTestingTimeTrypsinTrypsinogenapical membranechildren with cystic fibrosischymotrypsincystic fibrosis patientscytokinedesignimproved functioningin uteroin vivolight microscopymouse modelnovelnutritionpancreatic juicepublic health relevanceresponsetherapy 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(由申请方提供):胰腺受累很常见,大多数囊性纤维化(CF)患者的损伤进展为胰腺功能不全(PI)。目前,没有治疗方法可以阻止CF中胰腺疾病的进展,并且导致胰腺破坏的确切机制还不清楚。到目前为止,两个主要的障碍是人类胰腺的不可及性和缺乏合适的动物模型。我们生产了具有两个囊性纤维化跨膜传导调节因子(CFTR)等位基因的靶向破坏的猪(Sus scrofa)。这些动物的胰腺病变与患有CF的人类中发现的胰腺病变明显相似,并且它们的胰腺具有增加的炎性细胞数量和更高水平的促炎细胞因子IL-8。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的达到我们的目标:(1)确定CFTR-/-猪外分泌胰腺病变的个体发生;(2)确定CFTR在体内和体外调节外分泌胰腺功能中的作用。第一个目的是检验CF中的胰腺疾病在子宫内开始为腺泡栓并随着时间进展为腺泡细胞萎缩、导管扩张、粘液细胞化生和纤维化的假设。将使用组织病理学、酶表达、胰腺细胞标志物和微阵列基因分析来表征CF的新型猪模型的解剖学起源、疾病进展和病理生理学特征。将探讨炎症对胰腺病变发展和进展的影响。第二个目的是检验CFTR直接参与胰腺Cl-和HCO 3-分泌的假设。将使用CFTR-/-和CFTR+/+猪在体内(粪便脂肪和胰凝乳蛋白酶分析;收集胰液)和体外(原代猪导管上皮细胞培养物)确定CFTR在调节猪胰腺外分泌功能中的作用。本申请的目的是研究我们的新型CF猪模型中的胰腺病理生理学,并更好地了解导致CF中胰腺受累的病理生理学机制。我们的长期目标是设计创新的治疗方法,以保护胰腺功能,改善CF的生活质量,生长延迟和营养不良。公共卫生关系:胰腺受累是常见的,并且在大多数囊性纤维化(CF)患者中损伤进展为胰腺功能不全(PI)。目前,没有治疗方法可以阻止CF中胰腺疾病的进展,并且导致胰腺破坏的确切机制还不清楚。本申请的目的是充分表征我们的新型CF猪模型中的胰腺受累,并更好地理解CF中导致PI的病理生理机制。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Simplified and versatile method for isolation of high-quality RNA from pancreas.
- DOI:10.2144/0000113862
- 发表时间:2012-05
- 期刊:
- 影响因子:2.7
- 作者:Griffin M;Abu-El-Haija M;Abu-El-Haija M;Rokhlina T;Uc A
- 通讯作者:Uc A
Predicting the severity of pediatric acute pancreatitis: are we there yet?
预测小儿急性胰腺炎的严重程度:我们做到了吗?
- DOI:10.1097/mpg.0b013e318291ff40
- 发表时间:2013
- 期刊:
- 影响因子:2.9
- 作者:Uc,Aliye
- 通讯作者:Uc,Aliye
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{{ truncateString('Aliye Uc', 18)}}的其他基金
INSPPIRE to Study Pediatric Chronic Pancreatitis
INSPPIRE 研究小儿慢性胰腺炎
- 批准号:
9352341 - 财政年份:2015
- 资助金额:
$ 37.5万 - 项目类别:
INSPPIRE to Study Pediatric Chronic Pancreatitis
INSPPIRE 研究小儿慢性胰腺炎
- 批准号:
9045340 - 财政年份:2015
- 资助金额:
$ 37.5万 - 项目类别:
INSPPIRE to Study Pediatric Chronic Pancreatitis
INSPPIRE 研究小儿慢性胰腺炎
- 批准号:
9237999 - 财政年份:2015
- 资助金额:
$ 37.5万 - 项目类别:
INSPPIRE to Study Pediatric Chronic Pancreatitis
INSPPIRE 研究小儿慢性胰腺炎
- 批准号:
10012208 - 财政年份:2015
- 资助金额:
$ 37.5万 - 项目类别:
INSPPIRE TO STUDY ACUTE RECURRENT AND CHRONIC PANCREATITIS IN CHILDREN
启发研究儿童急性复发性和慢性胰腺炎
- 批准号:
8541852 - 财政年份:2012
- 资助金额:
$ 37.5万 - 项目类别:
INSPPIRE TO STUDY ACUTE RECURRENT AND CHRONIC PANCREATITIS IN CHILDREN
启发研究儿童急性复发性和慢性胰腺炎
- 批准号:
8854592 - 财政年份:2012
- 资助金额:
$ 37.5万 - 项目类别:
INSPPIRE TO STUDY ACUTE RECURRENT AND CHRONIC PANCREATITIS IN CHILDREN
启发研究儿童急性复发性和慢性胰腺炎
- 批准号:
8359486 - 财政年份:2012
- 资助金额:
$ 37.5万 - 项目类别:
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
- 批准号:
7697083 - 财政年份:2009
- 资助金额:
$ 37.5万 - 项目类别:
Regulation of heme uptake in intestinal epithelial cells
肠上皮细胞血红素摄取的调节
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Regulation of heme uptake in intestinal epithelial cells
肠上皮细胞血红素摄取的调节
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7190046 - 财政年份:2006
- 资助金额:
$ 37.5万 - 项目类别:
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