A Ginsenoside TMEM16A Potentiator for Cystic Fibrosis

人参皂苷 TMEM16A 治疗囊性纤维化的增效剂

基本信息

项目摘要

PROJECT SUMMARY Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel impedes mucus clearance and leads to the airway disease, cystic fibrosis (CF). New CFTR modulators improve mucociliary transport (MCT) and pathophysiologic manifestations of the disease in genetic mutation-specific patients, but do not completely restore airway function. We recently discovered ginsenosides derived from Korean Red Ginseng serve as potentiators of the Ca2+-activated Cl− channel (CaCC) [TMEM16A] and can restore MCT in vitro and in vivo through this alternative Cl- pathway. Yet, poor clinical trial results with activators of TMEM16A and a recently described role for the channel in mucus hypersecretion in infected airways has led to some to suggest that inhibiting TMEM16A is a better strategy. However, we hypothesize that potentiating TMEM16A, rather than channel activation through purinergic, intracellular Ca2+- driven pathways, will rescue MCT in infected CF airways. Specific Aim 1 will isolate the ginsenoside that most effectively potentiates TMEM16A and measure its effects on MCT parameters and mucus pathology. We anticipate finding the optimal ginsenoside through Ussing chamber and patch clamp experiments, while also measuring the impact on markers of MCT and mucus viscosity. Specific Aim 2 will assess whether a TMEM16A potentiator improves epithelial Cl- secretion, histopathology, and MCT parameters in infected CF rat airways. We will determine single dose pharmacokinetics for the selected ginsenoside and administer to Pseudomonas-infected CF rats to evaluate nasal potential difference, MCT, lung micro-CTs, histopathology, mucus properties (viscosity, solids, mass, density), and inflammatory cytokines. We will answer questions about the therapeutic utility of targeting the TMEM16A pathway and identify a new TMEM16A potentiator as an effective treatment for CF airway disease.
项目摘要 囊性纤维化跨膜传导调节因子(CFTR)Cl-通道功能障碍阻碍粘液 清除并导致气道疾病,囊性纤维化(CF)。新的CFTR调节剂改善粘膜纤毛 运输(MCT)和遗传突变特异性患者疾病的病理生理表现,但 不能完全恢复气道功能。我们最近发现了从朝鲜红中提取的皂甙 人参作为Ca 2+激活的Cl−通道(CaCC)的增强剂[TMEM 16 A],可以恢复MCT, 体外和体内通过这种替代Cl-途径。然而,TMEM 16 A激活剂的临床试验结果不佳, 并且最近描述了该通道在受感染的气道中粘液分泌过多中的作用, 这表明抑制TMEM 16 A是更好的策略。然而,我们假设增强TMEM 16 A, 而不是通过嘌呤能通道激活,细胞内Ca 2+驱动的途径,将拯救MCT, 感染CF气道。特异性目标1将分离最有效地增强TMEM 16 A和 测量其对MCT参数和粘液病理学的影响。我们期望找到最佳的 通过Ussing室和膜片钳实验,同时还测量了MCT对标记物的影响 和粘液粘度。具体目标2将评估TMEM 16 A增效剂是否改善上皮Cl- 分泌、组织病理学和MCT参数。我们将确定单剂量 药代动力学的选择,并给予假单胞菌感染的CF大鼠,以评估 鼻电位差、MCT、肺微CT、组织病理学、粘液性质(粘度、固体、质量, 密度)和炎性细胞因子。我们将回答有关靶向治疗效用的问题, TMEM 16 A通路,并确定一种新的TMEM 16 A增效剂作为CF气道疾病的有效治疗。

项目成果

期刊论文数量(0)
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Bradford Alan Woodworth其他文献

10:48: Spontaneous CSF Leaks: A Paradigm for Definitive Repair
  • DOI:
    10.1016/j.otohns.2007.06.031
  • 发表时间:
    2007-08-01
  • 期刊:
  • 影响因子:
  • 作者:
    Bradford Alan Woodworth;Anthony Alexander Prince;Alexander G. Chiu;Noam A. Cohen;David W. Kennedy;James N. Palmer
  • 通讯作者:
    James N. Palmer

Bradford Alan Woodworth的其他文献

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{{ truncateString('Bradford Alan Woodworth', 18)}}的其他基金

Ivacaftor for Acquired CFTR Dysfunction in Chronic Rhinosinusitis
Ivacaftor 治疗慢性鼻窦炎获得性 CFTR 功能障碍
  • 批准号:
    9324344
  • 财政年份:
    2016
  • 资助金额:
    $ 22.28万
  • 项目类别:
Chloride secretagogues for acquired CFTR dysfunction in chronic rhinosinusitis
氯化物促分泌剂治疗慢性鼻窦炎获得性 CFTR 功能障碍
  • 批准号:
    8233957
  • 财政年份:
    2011
  • 资助金额:
    $ 22.28万
  • 项目类别:
Chloride secretagogues for acquired CFTR dysfunction in chronic rhinosinusitis
氯化物促分泌剂治疗慢性鼻窦炎获得性 CFTR 功能障碍
  • 批准号:
    8620702
  • 财政年份:
    2011
  • 资助金额:
    $ 22.28万
  • 项目类别:
Chloride secretagogues for acquired CFTR dysfunction in chronic rhinosinusitis
氯化物促分泌剂治疗慢性鼻窦炎获得性 CFTR 功能障碍
  • 批准号:
    8028013
  • 财政年份:
    2011
  • 资助金额:
    $ 22.28万
  • 项目类别:
Chloride secretagogues for acquired CFTR dysfunction in chronic rhinosinusitis
氯化物促分泌剂治疗慢性鼻窦炎获得性 CFTR 功能障碍
  • 批准号:
    8433329
  • 财政年份:
    2011
  • 资助金额:
    $ 22.28万
  • 项目类别:
Core A: Cell Model and Evaluation Core
核心A:细胞模型和评估核心
  • 批准号:
    10246450
  • 财政年份:
    2007
  • 资助金额:
    $ 22.28万
  • 项目类别:
Core A: Cell Model and Evaluation Core
核心A:细胞模型和评估核心
  • 批准号:
    10468804
  • 财政年份:
    2007
  • 资助金额:
    $ 22.28万
  • 项目类别:

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