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Development of PAR2 Antagonists for Control of Asthma

Development of PAR2 Antagonists for Control of Asthma
开发用于控制哮喘的 PAR2 拮抗剂
批准号:
9592081
负责人:
Scott Boitano
金额:
$22.72万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-06-01 至 2020-05-31

项目摘要

项目成果

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中文摘要
翻译
项目摘要 过敏性哮喘的患病率正在增加,并由特定的环境暴露引发。来 在过去的几十年里,哮喘的治疗方法基本上没有改变, 在接受标准哮喘药物治疗的患者中,超过一半的患者的哮喘仍然不受控制。不像更 良性过敏原如花粉,哮喘相关过敏原(哮喘原;例如,某些真菌,蟑螂, 和尘螨)具有蛋白酶活性。哮喘原蛋白酶提供了多种机制, 过敏原活性,包括G蛋白偶联受体(GPCR)的直接激活,蛋白酶激活 受体2(PAR 2)。在小鼠模型中,PAR 2敲除可显著降低哮喘变应原诱导的哮喘 症状最近的报道表明,PAR 2中和抗体也可以有效地减少过敏原- 诱发哮喘症状。总之,PAR 2为药物发现提供了一个新的靶点,以控制 过敏性哮喘我们最近开发了一种有效的和特异性的PAR 2拮抗剂, 在体外的上皮PAR 2信号传导和在体内阻断PAR 2相关的疼痛反应。我们的初步数据显示, 实验室表明,C391可以有效减轻传统小鼠模型中过敏原诱导的哮喘。 在本申请中,我们建议优化C391用于药理学控制过敏性疾病的发展。 哮喘高度相关的体内模型。优化包括减小尺寸,改善吸收,分布, 代谢和毒性性能以及通过哮喘测量的改善的体内性能 高度相关的临床前模型中的症状控制。这些目标的实现将为我们提供一个巨大的前景, 临床上朝着开发一种新的哮喘治疗方法迈出了一步。
英文摘要
Project Abstract Allergic asthma is increasing in prevalence and triggered by specific environmental exposures. Over the past several decades asthma treatments have been largely unchanged and it is an unfortunate reality that asthma remains uncontrolled in more than half the patients receiving standard asthma medication. Unlike more benign allergens such as pollens, asthma-associated allergens (asthmagens; e.g., certain fungi, cockroaches, and dust mites) have protease activity. Asthmagen proteases provide multiple mechanisms for increased allergen activity including the direct activation of the G protein-coupled receptor (GPCR), Protease-activated receptor-2 (PAR2). In mouse models, knockout of PAR2 significantly reduces asthma allergen-induced asthma symptoms. Recent reports have shown that PAR2 neutralizing antibodies can also effectively reduce allergen- induced asthma symptoms. Taken together, PAR2 provides a novel target for drug discovery in the control of allergic asthma. We have recently developed a potent and specific PAR2 antagonist shown to block airway epithelial PAR2 signaling in vitro and block PAR2-associated pain response in vivo. Preliminary data from our laboratory suggests that C391 can effectively reduce allergen-induced asthma in conventional mouse models. In this application we propose to optimize C391 for pharmacological control of the development of allergic asthma in highly relevant in vivo models. Optimization includes reduced size, improved absorption, distribution, metabolism and toxicity performance as well as improved in vivo performance as measured by asthma symptom control in highly relevant pre-clinical models. The completion of these aims will provide a large pre- clinical step toward the development of a new class of asthma therapeutics.
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Development of small molecule Protease-activated-receptor-2 antagonists as oral asthma therapeutics
  • 批准号:
    10766584
  • 项目类别:
  • 资助金额:
    $30.0万
  • 财政年份:
    2023
  • 负责人:
    Scott Boitano
  • 依托单位:
Development of SP-A Derived Peptidomimetics for the Treatment of Asthma - Phase II
  • 批准号:
    10551972
  • 项目类别:
  • 资助金额:
    $195.56万
  • 财政年份:
    2022
  • 负责人:
    Scott Boitano
  • 依托单位:
Development of SP-A Derived Peptidomimetics for the Treatment of Asthma - Phase II
  • 批准号:
    10708853
  • 项目类别:
  • 资助金额:
    $147.82万
  • 财政年份:
    2022
  • 负责人:
    Scott Boitano
  • 依托单位:
Development of Small Molecule Antagonists of PAR-2 for treatment of asthma
  • 批准号:
    10326155
  • 项目类别:
  • 资助金额:
    $28.34万
  • 财政年份:
    2021
  • 负责人:
    Scott Boitano
  • 依托单位:
海外基金