Chloride Channels in Lung Development

肺部发育中的氯离子通道

基本信息

  • 批准号:
    7824125
  • 负责人:
  • 金额:
    $ 6.7万
  • 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:
    2009-06-01 至 2010-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Cystic Fibrosis (CF) is a life-limiting systemic inherited illness with a tremendous financial burden. Relentlessly progressive pulmonary disease is still the primary cause of the morbidity and mortality in CF. The cystic fibrosis transmembrane regulator (CFTR) is a cAMP-regulated chloride channel that is highly expressed in fetal airway epithelia. However, CFTR function is not required until after birth when it maintains periciliary fluid balance and sustains effective mucociliary clearance. After birth, and in the absence of CFTR-mediated chloride secretion, the epithelial sodium channel, ENaC, is unregulated and drives excessive sodium and fluid absorption. This dehydrates the airways and increases the viscosity of airways secretions, thereby impairing bacterial clearance. We have proposed that alternative chloride channels can be exploited to bypass the CFTR defect. We will test the hypothesis that over-expression and activation of the ClC-2 channel in the postnatal period will rescue the CF murine lung by restoring chloride secretion and down-regulation of ENaC. Our long term goal is to discover the technology and determine the mechanism that will allow compensation of the mutant CFTR with an endogenous gene product, ClC-2. Aim 1: To determine the sequence of protein interactions by which ClC2 is targeted to the plasma membrane. The hypothesis is that HSP90 complexes regulate apical plasma membrane expression of ClC-2. We demonstrate that HSP90 interacts with ClC-2 and we have developed the technology to identify ClC-2 and its binding partners on 2D gels followed by MALDI-TOF. The goal is to discover the factors that maximize surface ClC-2 expression and function. Aim 2: To determine whether ClC-2 and ENaC interact through Cl- current to modulate ion transport in the CF mouse lung. The hypothesis is that chloride conductance through ClC-2 will inhibit ENaC function. We predict that in CF mice, sustained activation of ClC-2 will decrease resting potential difference and the amiloride inhibited fraction of PD. Aim 3: To determine whether ClC-2 function can regulate the inflammatory response to infection or LPS challenge. The hypothesis is that stimulating ClC-2 expression and ClC-2 mediated chloride transport will restore normal levels of inflammatory responses in CF mice. These studies will produce the following novel contributions: 1) demonstration that an alternative chloride channel can bypass the CFTR defect in an animal model of CF: 2) dissemination and sharing of a novel epithelial-specific, doxycycline-regulated TET-On human ClC-2 mouse model; 3) assessment of two novel ClC-2 activators, from Sucampo Pharmaceuticals, for CF lung disease; and 4) techniques to induce and assess CFTR-mediated airways inflammation in CF mice. PUBLIC HEALTH RELEVANCE: We propose to test the hypothesis that over-expression and activation of pH- and voltage activated ClC-2 channels will rescue the cystic fibrosis mouse. Critical protein:protein interactions will be interrogated during trafficking of ClC-2 to apical membranes of airway epithelial cells. The product of this work will be a method of stimulating chloride transport to compensate for mutant CFTR, reduce sodium absorption and relieve airway inflammation in vivo.
描述(申请人提供):囊性纤维化(CF)是一种具有巨大经济负担的限制生命的全身性遗传病。顽固性进行性肺部疾病仍然是CF发病率和死亡率的主要原因。囊性纤维化跨膜调节因子(CFTR)是一种cAMP调节的氯离子通道,在胎儿呼吸道上皮细胞中高表达。然而,CFTR功能直到出生后才需要,那时它维持睫状液平衡并维持有效的粘液纤毛清除。出生后,在没有CFTR介导的氯离子分泌的情况下,上皮钠通道ENaC是不受调节的,并驱动过多的钠和液体吸收。这会使呼吸道脱水,增加呼吸道分泌物的粘度,从而损害细菌的清除。我们已经提出,可以利用替代的氯离子通道来绕过CFTR缺陷。我们将验证这一假设,即在出生后阶段过度表达和激活ClC-2通道将通过恢复氯的分泌和ENaC的下调来拯救CF小鼠的肺。我们的长期目标是发现这项技术,并确定允许用内源基因产物CLC-2补偿突变的CFTR的机制。目的1:确定Clc2靶向质膜的蛋白质相互作用序列。假设HSP90复合体调节CLC-2的顶端质膜表达。我们证明了HSP90与ClC-2相互作用,并开发了一种技术来鉴定ClC-2及其在2D凝胶上的结合伙伴,随后进行了MALDI-TOF。我们的目标是发现使表面ClC-2表达和功能最大化的因素。目的:探讨ClC-2和ENaC是否通过氯电流相互作用调节肺组织离子转运。假设通过ClC-2的氯离子电导将抑制ENaC功能。我们预测,在CF小鼠中,ClC-2的持续激活将降低静息电位差,而阿米洛利则抑制PD的部分。目的:探讨ClC-2功能是否对感染或内毒素攻击的炎症反应具有调节作用。假设刺激ClC-2的表达和ClC-2介导的氯离子转运将恢复CF小鼠正常的炎症反应水平。这些研究将产生以下新的贡献:1)证明在CF的动物模型中,替代的氯通道可以绕过CFTR缺陷:2)传播和分享一种新型的上皮特异性的、多西环素调节的Tet-on人类CLC-2小鼠模型;3)评估Sucampo制药公司的两种新的CLC-2激活剂,用于治疗CF肺部疾病;以及4)诱导和评估CFTR介导的CF小鼠呼吸道炎症的技术。公共卫生相关性:我们建议检验这样一种假设,即过度表达和激活pH和电压激活的ClC-2通道将拯救囊性纤维化小鼠。关键蛋白质:在将ClC-2转运到呼吸道上皮细胞顶膜的过程中,将询问蛋白质之间的相互作用。这项工作的成果将是一种刺激氯运输的方法,以补偿突变的CFTR,减少钠的吸收,并减轻体内的呼吸道炎症。

项目成果

期刊论文数量(0)
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Pamela L. Zeitlin其他文献

Net benefit of ivacaftor during prolonged tezacaftor/elexacaftor exposure emin vitro/em
  • DOI:
    10.1016/j.jcf.2022.02.011
  • 发表时间:
    2022-07-01
  • 期刊:
  • 影响因子:
    6.000
  • 作者:
    Ciaran A. Shaughnessy;Pamela L. Zeitlin;Preston E. Bratcher
  • 通讯作者:
    Preston E. Bratcher
The Changing Face of Cystic Fibrosis: An Update for Anesthesiologists.
囊性纤维化的变化:麻醉师的更新。
  • DOI:
    10.1213/ane.0000000000005856
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    5.7
  • 作者:
    Amy J. Lee;J. Huffmyer;Eryn L Thiele;Pamela L. Zeitlin;D. Chatterjee
  • 通讯作者:
    D. Chatterjee
717. VCP Short Hairpin RNA Rescues ΔF508- CFTR and Suppresses IL8 Levels: Therapeutic Implications in Cystic Fibrosis
  • DOI:
    10.1016/j.ymthe.2006.08.796
  • 发表时间:
    2006-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Neeraj Vij;Shengyun Fang;Pamela L. Zeitlin
  • 通讯作者:
    Pamela L. Zeitlin

Pamela L. Zeitlin的其他文献

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{{ truncateString('Pamela L. Zeitlin', 18)}}的其他基金

Mechanism of Prostone Activation During CFTR Modulation
CFTR 调节过程中前列酮激活的机制
  • 批准号:
    10687435
  • 财政年份:
    2022
  • 资助金额:
    $ 6.7万
  • 项目类别:
Ph 1-2 Study of Glycerolphenylbutyrate for Cystic Fibrosis IND 125,124 (12/5/15)
Ph 1-2 甘油苯基丁酸酯治疗囊性纤维化的研究 IND 125,124 (12/5/15)
  • 批准号:
    9322858
  • 财政年份:
    2016
  • 资助金额:
    $ 6.7万
  • 项目类别:
Phase 2 study of digitoxin for cystic fibrosis - IND 70279
洋地黄毒苷治疗囊性纤维化的 2 期研究 - IND 70279
  • 批准号:
    7566224
  • 财政年份:
    2008
  • 资助金额:
    $ 6.7万
  • 项目类别:
Phase 2 study of digitoxin for cystic fibrosis - IND 70279
洋地黄毒苷治疗囊性纤维化的 2 期研究 - IND 70279
  • 批准号:
    7689355
  • 财政年份:
    2008
  • 资助金额:
    $ 6.7万
  • 项目类别:
Phase 2 study of digitoxin for cystic fibrosis - IND 70279
洋地黄毒苷治疗囊性纤维化的 2 期研究 - IND 70279
  • 批准号:
    8238123
  • 财政年份:
    2008
  • 资助金额:
    $ 6.7万
  • 项目类别:
Phase 2 Study of Digitoxin for the Treatment of Cystic Fibrosis
洋地黄毒素治疗囊性纤维化的 2 期研究
  • 批准号:
    8747904
  • 财政年份:
    2007
  • 资助金额:
    $ 6.7万
  • 项目类别:
CAMP STIMULATED SWEAT RATE IN CYSTIC FIBROSIS
囊性纤维化中 CAMP 刺激出汗率
  • 批准号:
    7604524
  • 财政年份:
    2006
  • 资助金额:
    $ 6.7万
  • 项目类别:
TRANSEPITHELIAL POTENTIAL DIFFERENCE IN PTS W/ VARIANTS OF CYSTIC FIBROSIS (CF)
囊性纤维化 (CF) 变体 PTS 的跨上皮电位差
  • 批准号:
    7604525
  • 财政年份:
    2006
  • 资助金额:
    $ 6.7万
  • 项目类别:
ASSESSMENT OF INDUCED SPUTUM
诱发痰的评估
  • 批准号:
    7604596
  • 财政年份:
    2006
  • 资助金额:
    $ 6.7万
  • 项目类别:
A PHASE 2 STUDY OF PTC124 FOR CYSTIC FIBROSIS
PTC124 治疗囊性纤维化的 2 期研究
  • 批准号:
    7604667
  • 财政年份:
    2006
  • 资助金额:
    $ 6.7万
  • 项目类别:

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