Conducting Airway Cellular Targets Required for Complementation of CF Lung Disease

传导补充 CF 肺病所需的气道细胞靶点

基本信息

  • 批准号:
    10470338
  • 负责人:
  • 金额:
    $ 48.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-01 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

Project-3 Summary Complexities in CFTR-expressing epithelial cells of the conducting human and mouse airway were recently revealed by single-cell RNA sequencing (scRNAseq). These studies identified the ionocyte, an infrequent cell type that expresses the majority of CFTR in the proximal airway and submucosal gland ducts. They also showed that the repertoire of ion channels in the ionocyte is uniquely suited to potentially regulate airway pH. However, whether only ionocytes contribute to innate immunity and clearance in the airways remains to be determined; it is possible that other airway cell types, such as ciliated cells, express CFTR at levels that are below the detection limits of scRNAseq yet are functionally important in the pathogenesis of CF lung disease. Deeper knowledge of CFTR cellular physiology in the airway will greatly enhance our understanding of CF pathogenesis, while also informing the cellular targets for gene therapy of CF lung disease. The proposed project will focus on understanding the cellular functions of CFTR in ionocytes and ciliated cells, and whether CFTR expression in each of these cell types is required or sufficient to prevent CF lung disease. Our hypotheses will be tested in genetic ferret models, a species that more accurately reflects human CF lung disease than mice. These studies are possible because of the creation of several new genetic ferret models that can conditionally (in specific cell types) inactivate CFTR expression on a wild-type (WT) background or reactivate CFTR expression on a CF background. Both of these strategies use CreERT2 technologies and enable lineage tracing of the targeted cells in vivo using a fluorescent Cre-reporter. Additionally, we propose to generate a new genetic ferret model in which CFTR is overexpressed specifically in ciliated cells, to test whether high-level ectopic expression therein is sufficient to protect from CF lung disease. Key goals of this project are to: 1) define the contributions of CFTR expression in ionocytes and ciliated cells to CF lung pathogenesis, 2) determine the half-lives of ionocytes and ciliated cells in the CF and non-CF airway, and 3) determine the extent to which CFTR expression in ionocytes and ciliated cells contributes to the regulation of disease-relevant features of the airway surface liquid (ASL) (i.e. volume, antibacterial activity, chloride and bicarbonate transport, and pH) and to mucociliary clearance. Each of these goals draws on the unique ability of the Engelhardt laboratory to genetically engineer transgenic ferrets to temporally regulate CFTR expression in specific cell types and to test these models for CF-relevant functional endpoints in vivo and in vitro. The proposed study is the first to use state-of-art functional genetic approaches in a non-mouse species to tackle difficult cell biology questions relating to CFTR function in the airway and CF lung pathogenesis. This research is expected to significantly enhance the field's ability to develop effective genetic therapies for CF lung disease.
项目-3摘要 近几年来,人和小鼠呼吸道上皮细胞表达CFTR的复杂性 通过单细胞RNA测序(ScRNAseq)揭示。这些研究确定了离子细胞,一种罕见的细胞 在近端呼吸道和粘膜下腺导管中表达大多数CFTR的类型。他们也 结果表明,离子细胞中的离子通道谱系唯一适合于潜在地调节呼吸道pH。 然而,是否只有离子细胞对呼吸道的先天免疫和清除起作用还有待进一步研究。 其他类型的呼吸道细胞,如纤毛细胞,可能在 在scRNAseq的检测下限以下,但在CF肺部疾病的发病机制中仍具有重要的功能。 更深入地了解CFTR在呼吸道中的细胞生理学将极大地增强我们对CF的理解 同时也为肺纤维化的基因治疗提供了细胞靶点。建议数 该项目将侧重于了解CFTR在离子细胞和纤毛细胞中的细胞功能,以及 CFTR在这些细胞类型中的每一种中的表达都是预防CF肺部疾病所必需的或足够的。我们的 假说将在遗传雪貂模型中得到验证,这是一种更准确地反映人类CF肺的物种 疾病比老鼠还多。这些研究是可能的,因为创造了几个新的遗传雪貂模型 可以有条件地(在特定细胞类型中)在野生型(WT)背景下灭活CFTR表达,或者 在CF背景下重新激活CFTR表达。这两种策略都使用CreERT2技术和 使用荧光Cre-Report实现体内靶细胞的谱系追踪。此外,我们建议 建立一种新的遗传雪貂模型,其中cftr在纤毛细胞中特异地过表达,以进行测试 其高水平的异位表达是否足以保护其免受肺纤维化的侵袭。这项工作的主要目标 项目是:1)确定CFTR在离子细胞和纤毛细胞中的表达在CFF肺中的作用 发病机制,2)决定CF和非CF气道中离子细胞和纤毛细胞的半衰期,以及3) 确定CFTR在离子细胞和纤毛细胞中的表达在多大程度上有助于调节 与疾病相关的呼吸道表面液体(ASL)特征(即体积、抗菌活性、氯化物和 碳酸氢盐的运输,和pH)和粘液纤毛清除。这些目标中的每一个都依赖于 恩格尔哈特实验室对转基因雪貂进行基因工程,以暂时调节CFTR在 并在体内和体外测试这些模型中与CF相关的功能端点。这个 提出的研究是第一次在非小鼠物种中使用最先进的功能遗传学方法来处理 与CFTR在呼吸道中的功能和CF肺发病机制相关的疑难细胞生物学问题。这项研究 预计将显著提高该领域开发治疗慢性萎缩性肺病的有效基因疗法的能力。

项目成果

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JOHN F ENGELHARDT其他文献

JOHN F ENGELHARDT的其他文献

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{{ truncateString('JOHN F ENGELHARDT', 18)}}的其他基金

Biology of Submucosal Gland Stem Cells in the Airway
气道粘膜下腺干细胞的生物学
  • 批准号:
    10516449
  • 财政年份:
    2022
  • 资助金额:
    $ 48.65万
  • 项目类别:
National Ferret Research and Resource Institute (NFRRI) at University of Iowa
爱荷华大学国家雪貂研究与资源研究所 (NFRRI)
  • 批准号:
    10596901
  • 财政年份:
    2022
  • 资助金额:
    $ 48.65万
  • 项目类别:
Biology of Submucosal Gland Stem Cells in the Airway
气道粘膜下腺干细胞的生物学
  • 批准号:
    10649543
  • 财政年份:
    2022
  • 资助金额:
    $ 48.65万
  • 项目类别:
Early Pathogenesis of Cystic Fibrosis Related Diabetes
囊性纤维化相关糖尿病的早期发病机制
  • 批准号:
    10599931
  • 财政年份:
    2021
  • 资助金额:
    $ 48.65万
  • 项目类别:
Early Pathogenesis of Cystic Fibrosis Related Diabetes
囊性纤维化相关糖尿病的早期发病机制
  • 批准号:
    10397094
  • 财政年份:
    2021
  • 资助金额:
    $ 48.65万
  • 项目类别:
Conducting Airway Cellular Targets Required for Complementation of CF Lung Disease
传导补充 CF 肺病所需的气道细胞靶点
  • 批准号:
    10677622
  • 财政年份:
    2020
  • 资助金额:
    $ 48.65万
  • 项目类别:
Conducting Airway Cellular Targets Required for Complementation of CF Lung Disease
传导补充 CF 肺病所需的气道细胞靶点
  • 批准号:
    10248531
  • 财政年份:
    2020
  • 资助金额:
    $ 48.65万
  • 项目类别:
Conducting Airway Cellular Targets Required for Complementation of CF Lung Disease
传导补充 CF 肺病所需的气道细胞靶点
  • 批准号:
    10024668
  • 财政年份:
    2020
  • 资助金额:
    $ 48.65万
  • 项目类别:
National Ferret Resource and Research Center on Lung Disease
国家雪貂资源与肺部疾病研究中心
  • 批准号:
    8751112
  • 财政年份:
    2014
  • 资助金额:
    $ 48.65万
  • 项目类别:
National Ferret Resource and Research Center on Lung Disease
国家雪貂资源与肺部疾病研究中心
  • 批准号:
    9283593
  • 财政年份:
    2014
  • 资助金额:
    $ 48.65万
  • 项目类别:

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