CFTR and acid-base transporters in regenerating intestinal crypts

CFTR 和酸碱转运蛋白在肠隐窝再生中的作用

基本信息

  • 批准号:
    8825909
  • 负责人:
  • 金额:
    $ 35.72万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1995
  • 资助国家:
    美国
  • 起止时间:
    1995-08-01 至 2018-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Crypts harbor the stem and transit amplifying cell compartments of intestinal epithelium. However, little is known of crypt cellular physiology due to inaccessibility in vivo and past failures of primary culture. Understanding regulation of intracellular pH (pHi) is particularly critical because it affects cell proliferation/ apoptosis an, therefore, processes of tissue regeneration and the potential for malignant transformation. The genetic disease cystic fibrosis (CF) caused by mutations of the HCO3- exporter CFTR exemplifies this concept by demonstrating an alkaline pHi, crypt hyperplasia and a six-fold increase in gastrointestinal neoplasia incidence. We hypothesize that Cftr normally sets the upper limit of crypt cell alkalinity which provides a negative control over the proliferation process. Crypt proliferation is maintained by extracellular Wnt signaling that canonically regulates the transcriptional cofactor of proliferation, ß-catenin, and other processes of epithelial morphogenesis. Little is known about how pHi affects Wnt signaling in crypts, although studies in non-mammalian systems indicate that an alkaline pHi increases membrane localization of the Wnt transducer Disheveled (Dvl) and thereby its interactions with Wnt receptors. We hypothesize that crypt hyperplasia in CF results from an alkaline pHi which increases Dvl transduction of Wnt/ß-catenin signaling and other processes of cell migration/epithelial morphogenesis. In normal intestine, rapid crypt proliferation makes crypt progenitor cells susceptible to off-target effects of chemotherapy/radiation, resulting in crypt damage and the symptoms associated with intestinal mucositis. We hypothesize that pharmacological control of pHi in crypt epithelium can be used to indirectly manipulate cell proliferation to minimize intestinal mucositis. Breakthroughs in developmental biology provide a model of regenerating crypt organoids ('enteroids') in 3D gel culture that we have adapted for studies of intestine from wild-type (WT) and Cftr knockout (KO) mice. Extensive preliminary studies have validated the in vivo fidelity of enteroids and developed techniques that provide remarkable access for imaging, electrophysiology and biochemistry of the gel cultures. In Specific Aim 1, acid-base transporters involved in pHi regulation in transit amplifying cells and stem cells of the crypt will be identified and evaluated for pHi regulation in WT and Cftr KO intestine. Specific Aim 2 will test the hypothesis that cell alkalinity in the Cftr KO crypt increaes membrane association of Dvl thereby facilitating canonical Wnt/ß-catenin signaling for proliferation and noncanonical pathways for increased cell migration and epithelial morphogenesis. Specific Aim 3 will explore pharmacological manipulation of Cftr and acid-base transporters to slow crypt proliferation during the damage phase and increase crypt proliferation during the repair phase of chemotherapy/radiation. The overall objective is to elucidate the pHi physiology of Wnt signaling in crypt progenitor cells, thereby advancing knowledge of pre-neoplastic conditions and introducing a novel therapeutic strategy for controlling gastrointestinal mucositis after chemotherapy/radiation insult.
描述(由申请方提供):隐窝包含肠上皮的干细胞和运输放大细胞区室。然而,由于在体内的不可及性和过去的原代培养的失败,对隐窝细胞生理学知之甚少。了解细胞内pH(pHi)的调节尤其重要,因为它影响细胞增殖/细胞凋亡,从而影响组织再生过程和恶性转化的可能性。由HCO 3-输出者CFTR突变引起的遗传性疾病囊性纤维化(CF)通过证明碱性pHi、隐窝增生和胃肠道肿瘤发生率增加6倍来证实这一概念。我们假设Cftr通常设定了隐窝细胞碱度的上限,这为增殖过程提供了阴性对照。隐窝增殖由细胞外Wnt信号传导维持,所述信号传导典型地调节增殖的转录辅因子、β-连环蛋白和上皮形态发生的其他过程。关于pHi如何影响隐窝中的Wnt信号传导知之甚少,尽管在非哺乳动物系统中的研究表明碱性pHi增加Wnt转导子Disheveled(Dvl)的膜定位,从而增加其与Wnt受体的相互作用。我们假设CF中的隐窝增生是由碱性pHi引起的,碱性pHi增加了Wnt/β-连环蛋白信号传导的Dvl转导和细胞迁移/上皮形态发生的其他过程。在正常肠中,快速的隐窝增殖使隐窝祖细胞对化疗/放疗的脱靶效应敏感,导致隐窝损伤和与肠粘膜炎相关的症状。我们假设,药理学控制的pHi在隐窝上皮细胞可以用来间接操纵细胞增殖,以尽量减少肠粘膜炎。发育生物学中的突破提供了在3D凝胶培养中再生隐窝类器官(“肠类”)的模型,我们已经将其适用于来自野生型(WT)和Cftr敲除(KO)小鼠的肠的研究。广泛的初步研究已经验证了在体内保真度的肠和开发的技术,提供显着的成像,电生理和生物化学的凝胶培养。在特定目标1中,将鉴定参与转运放大细胞和隐窝干细胞中pHi调节的酸碱转运蛋白,并评价WT和Cftr KO肠道中的pHi调节。具体目标2将检验以下假设:Cftr KO隐窝中的细胞碱性增加Dvl的膜结合,从而促进用于增殖的经典Wnt/β-连环蛋白信号传导和用于增加细胞迁移和上皮形态发生的非经典途径。具体目标3将探索Cftr和酸碱转运蛋白的药理学操作,以减缓损伤阶段的隐窝增殖,并增加化疗/放疗修复阶段的隐窝增殖。总体目标是阐明隐窝祖细胞中Wnt信号传导的pHi生理学,从而推进肿瘤前状态的知识,并引入一种新的治疗策略来控制化疗/放射损伤后的胃肠道粘膜炎。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Goblet Cell Hyperplasia is not Epithelial-Autonomous in the Cftr Knockout Intestine.
Phosphodiesterase 5 inhibitors and cystic fibrosis: correcting chloride channel dysfunction.
磷酸二酯酶 5 抑制剂和囊性纤维化:纠正氯离子通道功能障碍。
Cftr Modulates Wnt/β-Catenin Signaling and Stem Cell Proliferation in Murine Intestine.
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LANE L CLARKE其他文献

LANE L CLARKE的其他文献

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{{ truncateString('LANE L CLARKE', 18)}}的其他基金

CFTR AND DUODENAL ANION TRANSPORT
CFTR 和十二指肠阴离子转运
  • 批准号:
    6680916
  • 财政年份:
    1995
  • 资助金额:
    $ 35.72万
  • 项目类别:
CFTR and acid-base transporters in regenerating intestinal crypts
CFTR 和酸碱转运蛋白在肠隐窝再生中的作用
  • 批准号:
    8292807
  • 财政年份:
    1995
  • 资助金额:
    $ 35.72万
  • 项目类别:
CFTR and acid-base transporters of intestinal epithelia
CFTR 和肠上皮酸碱转运蛋白
  • 批准号:
    7261910
  • 财政年份:
    1995
  • 资助金额:
    $ 35.72万
  • 项目类别:
CFTR AND ALIMENTARY EPITHELIAL ACID/ BASE TRANSPORT
CFTR 和消化道上皮酸/碱转运
  • 批准号:
    2149287
  • 财政年份:
    1995
  • 资助金额:
    $ 35.72万
  • 项目类别:
CFTR AND ALIMENTARY EPITHELIAL ACID/ BASE TRANSPORT
CFTR 和消化道上皮酸/碱转运
  • 批准号:
    2749527
  • 财政年份:
    1995
  • 资助金额:
    $ 35.72万
  • 项目类别:
CFTR and acid-base transporters of intestinal epithelia
CFTR 和肠上皮酸碱转运蛋白
  • 批准号:
    7147394
  • 财政年份:
    1995
  • 资助金额:
    $ 35.72万
  • 项目类别:
CFTR AND DUODENAL ANION TRANSPORT
CFTR 和十二指肠阴离子转运
  • 批准号:
    6476213
  • 财政年份:
    1995
  • 资助金额:
    $ 35.72万
  • 项目类别:
CFTR and acid-base transporters in regenerating intestinal crypts
CFTR 和酸碱转运蛋白在肠隐窝再生中的作用
  • 批准号:
    8638942
  • 财政年份:
    1995
  • 资助金额:
    $ 35.72万
  • 项目类别:
CFTR AND ALIMENTARY EPITHELIAL ACID/ BASE TRANSPORT
CFTR 和消化道上皮酸/碱转运
  • 批准号:
    2458862
  • 财政年份:
    1995
  • 资助金额:
    $ 35.72万
  • 项目类别:
CFTR AND DUODENAL ANION TRANSPORT
CFTR 和十二指肠阴离子转运
  • 批准号:
    6285005
  • 财政年份:
    1995
  • 资助金额:
    $ 35.72万
  • 项目类别:

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