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

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):胰腺受累是常见的,大多数囊性纤维化患者(CF)的损伤发展为胰腺功能不全(PI)。目前,尚无治疗方法来阻止CF中胰腺疾病的进展,导致胰腺破坏的确切机制并不理解。到目前为止,胰腺在人类中的两个主要障碍是无法访问的,并且缺乏合适的动物模型。我们产生了猪(SUS SCROFA),并靶向两种囊性纤维化跨膜电导调节剂(CFTR)等位基因。这些动物的胰腺病变与CF的人类发现明显相似,其胰腺的炎性细胞数量增加,促炎细胞因子的水平较高,IL-8。该项目的目的是充分表征CFTR - / - Pig Pancreas的解剖学和生理特征,并利用从该模型获得的数据来阐明人类中胰腺疾病的病理生理学。我们计划以以下特定目的达到目标:(1)确定CFTR - / - 猪中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中的作用。第一个目的将检验以下假设:CF中的胰​​腺疾病始于子宫内的腺泡插头,并且随着时间的流逝而发展为腺泡细胞萎缩,导管扩张,粘液细胞化生和纤维化。新型CF猪模型的解剖学起源,疾病进展和病理生理特征将使用组织病理学,酶表达,胰腺细胞标记和微阵列基因分析来表征。炎症对胰腺病变的发育和进展的影响将探讨。第二个目标将检验CFTR直接参与胰腺CL-和HCO3-分泌的假设。 CFTR在调节猪的外分泌胰腺功能中的作用将在体内确定(分析粪便脂肪和胰蛋白酶蛋白;胰腺液的收集)和体外(使用CFTR-和CFTR-和CFTR+/+ Pigs的体外(原发性猪内皮细胞培养)。该应用的目的是在我们新颖的CF猪模型中研究胰腺病理生理学,并更好地了解导致CF胰腺参与的病理生理机制。 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.公共卫生相关性:胰腺参与很普遍,大多数囊性纤维化患者(CF)的损伤发展为胰腺功能不全(PI)。目前,尚无治疗方法来阻止CF中胰腺疾病的进展,导致胰腺破坏的确切机制并不理解。该应用的目的是充分表征我们新型CF猪模型中胰腺的参与,并更好地了解导致CF中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?
Exercise Intolerance, Malnutrition, Abnormal Sweat Chloride Levels, and Two CFTR Mutations: Is It Cystic Fibrosis?
  • DOI:
    10.1016/j.pedhc.2014.05.010
  • 发表时间:
    2015-03-01
  • 期刊:
  • 影响因子:
    2.8
  • 作者:
    Com, Gulnur;Uc, Aliye
  • 通讯作者:
    Uc, Aliye
共 3 条
  • 1
前往

Aliye Uc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
    9352341
  • 财政年份:
    2015
  • 资助金额:
    $ 37.5万
    $ 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
    9045340
  • 财政年份:
    2015
  • 资助金额:
    $ 37.5万
    $ 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
    9237999
  • 财政年份:
    2015
  • 资助金额:
    $ 37.5万
    $ 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
    10012208
  • 财政年份:
    2015
  • 资助金额:
    $ 37.5万
    $ 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
    8541852
  • 财政年份:
    2012
  • 资助金额:
    $ 37.5万
    $ 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
    8854592
  • 财政年份:
    2012
  • 资助金额:
    $ 37.5万
    $ 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
    8359486
  • 财政年份:
    2012
  • 资助金额:
    $ 37.5万
    $ 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
    7697083
  • 财政年份:
    2009
  • 资助金额:
    $ 37.5万
    $ 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
  • 批准号:
    7018313
    7018313
  • 财政年份:
    2006
  • 资助金额:
    $ 37.5万
    $ 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
  • 批准号:
    7190046
    7190046
  • 财政年份:
    2006
  • 资助金额:
    $ 37.5万
    $ 37.5万
  • 项目类别:

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