Novel Therapies for Chlorine-Induced Lung Injury

氯引起的肺损伤的新疗法

基本信息

  • 批准号:
    7666141
  • 负责人:
  • 金额:
    $ 39.84万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-09-29 至 2011-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Acute high-level exposures to chemicals that damage the respiratory tract can cause life-threatening lung injury. Chlorine gas is a highly toxic respiratory irritant that when inhaled causes cellular injury, alveolar- capillary barrier disruption, inflammation, and pulmonary edema. We are investigating mechanisms by which G proteins, which are ubiquitous intracellular signaling molecules, regulate lung injury, inflammation, and repair. During the course of the proposed research we will investigate how G protein-mediated signaling pathways regulate injury and inflammation that are induced when lungs, or lung cells, are exposed to chlorine gas. We will then apply the information gained from these studies to develop novel treatment strategies based on modulation of G protein function to ameliorate acute lung injury. G protein coupled receptors (GPCRs), which control cellular homeostasis and responses to environmental stimuli, are activated by a variety of neuropeptides, inflammatory mediators, and hormones that are released following tissue injury. GPCRs activate intracellular signaling pathways by stimulating G proteins that have been classified into four families: Gq, Gs, Gj, and Gi2. We have observed that activation of Gq in lung epithelial cells stimulates proinflammatory gene expression, whereas activation of Gs promotes increased survival following injury. In the proposed experiments, we will use manipulation of Gq and Gs signaling pathways as potential therapeutic measures to treat acute lung injury induced by inhalation of chlorine gas. In Specific Aim 1 we will examine mechanisms by which Gq signaling promotes activation of the proinflammatory transcription factor NF-KB and Gs inhibits chlorine toxicity in cultured epithelial and endothelial cells. In Specific Aim 2, we will determine, using an inducible, cell-specific knockout mouse model, whether Gq signaling in lung epithelial cells is a therapeutic target for ameliorating acute lung injury. In Specific Aim 3, we will develop treatment strategies, including cell-soluble Gq inhibitory peptides and Gq siRNA, for chlorine-induced lung injury based on inhibition of Gq function. In Specific Aim 4, we will optimize the in vivo delivery of therapeutic agents for chlorine-induced lung injury based on inhibition of Gq function and stimulation signaling pathways downstream of Gs. This application is submitted in response to RFA-NS-06-004, "Countermeasures Against Chemical Threats." The proposed experiments are designed to understand how inhalation of a toxic chemical injures the lung and, based on this information, to develop novel ways to treat or prevent acute lung injury. This type of research is sought through the RFA because of concerns that U. S. civilians could be adversely affected by highly toxic chemicals released intentionally in terrorist attacks or unintentionally in industrial accidents or natural disasters.
描述(由申请人提供):急性高级暴露于损害呼吸道的化学物质会导致威胁生命的肺损伤。氯气是一种剧毒呼吸道刺激性,当吸入时会导致细胞损伤,肺泡毛细管屏障破坏,炎症和肺水肿。我们正在研究,G蛋白(无处不在的细胞内信号分子)调节肺损伤,炎症和修复的机制。在拟议的研究过程中,我们将研究G蛋白介导的信号通路如何调节肺或肺细胞时诱导的损伤和炎症。然后,我们将利用这些研究获得的信息来开发基于G蛋白功能的调节来制定新的治疗策略,以改善急性肺损伤。控制细胞稳态和对环境刺激的反应的G蛋白偶联受体(GPCR)被多种神经肽,炎症介质和激素激活,这些神经肽和激素在组织损伤后释放。 GPCR通过刺激已分类为四个家族的G蛋白来激活细胞内信号通路:GQ,GS,GJ和GI2。我们已经观察到,肺上皮细胞中GQ的激活刺激促炎基因的表达,而GS的激活促进了损伤后的生存率增加。在拟议的实验中,我们将使用对GQ和GS信号途径的操纵作为治疗氯气吸入诱导的急性肺损伤的潜在治疗措施。在特定目标1中,我们将研究GQ信号传导促进促炎转录因子NF-KB的激活的机制,而GS抑制了培养的上皮细胞和内皮细胞中的氯毒性。在特定目标2中,我们将使用诱导的,特异性的敲除小鼠模型来确定肺上皮细胞中的GQ信号是否是改善急性肺损伤的治疗靶标。在特定的目标3中,我们将基于GQ功能的抑制作用,制定用于氯诱导的肺损伤的治疗策略。在特定目标4中,我们将根据GQ功能的抑制和GS下游的刺激信号通路,优化氯诱导的肺损伤的治疗剂的体内递送。该申请是针对RFA-NS-06-004的“反对化学威胁的对策”提交的。拟议的实验旨在了解对肺部有毒化学损伤的吸入如何,并基于此信息开发新的方法来治疗或预防急性肺损伤。通过RFA寻求这种类型的研究,因为担心美国平民可能会受到有意在恐怖袭击中释放的高毒化学物质或在工业事故或自然灾害中无意中释放的剧毒化学物质的影响。

项目成果

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Gary W. Hoyle其他文献

Gary W. Hoyle的其他文献

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{{ truncateString('Gary W. Hoyle', 18)}}的其他基金

PILOT PROJECT
试点项目
  • 批准号:
    10217140
  • 财政年份:
    2020
  • 资助金额:
    $ 39.84万
  • 项目类别:
Treatment of persistent chlorine-induced small airway disease
持续性氯引起的小气道疾病的治疗
  • 批准号:
    9207953
  • 财政年份:
    2016
  • 资助金额:
    $ 39.84万
  • 项目类别:
Countermeasures for chlorine-induced airway fibrosis
氯诱发气道纤维化的对策
  • 批准号:
    8550807
  • 财政年份:
    2012
  • 资助金额:
    $ 39.84万
  • 项目类别:
Countermeasures for chlorine-induced airway fibrosis
氯诱发气道纤维化的对策
  • 批准号:
    8898799
  • 财政年份:
    2012
  • 资助金额:
    $ 39.84万
  • 项目类别:
Countermeasures for chlorine-induced airway fibrosis
氯诱发气道纤维化的对策
  • 批准号:
    8332591
  • 财政年份:
    2012
  • 资助金额:
    $ 39.84万
  • 项目类别:
Repair of Airway Epithelium Following Chlorine Lung Injury
氯肺损伤后气道上皮的修复
  • 批准号:
    8146941
  • 财政年份:
    2010
  • 资助金额:
    $ 39.84万
  • 项目类别:
Repair of Airway Epithelium Following Chlorine Lung Injury
氯肺损伤后气道上皮的修复
  • 批准号:
    8020447
  • 财政年份:
    2010
  • 资助金额:
    $ 39.84万
  • 项目类别:
Novel Therapies for Chlorine-Induced Lung Injury
氯引起的肺损伤的新疗法
  • 批准号:
    7560245
  • 财政年份:
    2006
  • 资助金额:
    $ 39.84万
  • 项目类别:
Novel Therapies for Chlorine-Induced Lung Injury
氯引起的肺损伤的新疗法
  • 批准号:
    8144562
  • 财政年份:
    2006
  • 资助金额:
    $ 39.84万
  • 项目类别:
Novel Therapies for Chlorine-Induced Lung Injury
氯引起的肺损伤的新疗法
  • 批准号:
    7447420
  • 财政年份:
    2006
  • 资助金额:
    $ 39.84万
  • 项目类别:

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发现创伤后头痛的新靶标
  • 批准号:
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  • 财政年份:
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  • 财政年份:
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