Inducible epithelial antiviral resistance to prevent asthma

诱导上皮抗病毒耐药性预防哮喘

基本信息

批准号：
8569065
负责人：
Scott E. Evans
金额：
$ 240万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2018-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Increasing millions of Americans suffer from poorly controlled asthma. Because eosinophilic and neutrophilic inflammation are hallmarks of disease, anti-inflammatory drugs are the mainstay of therapy, though they do not retard disease progression. Viral infections cause most exacerbations and result in asthma progression, yet are not targeted in asthma guidelines. Rather, immunosuppressive therapies enhance viral susceptibility. Lung epithelial cells are the primary targets of most respiratory viruses, are critcal to asthma pathogenesis, and are required for respiratory virus clearance. It has recently been shown that lung epithelial cells can be therapeutically stimulated to broadly protect against letha pneumonias, including viral infections. Accordingly, it is hypothesized that evoking a protective local antiviral immune response in the lungs, rather than indiscriminate suppression of all inflammation, will prevent asthma exacerbations and reduce progression. Inducible resistance to viruses has been shown to persist despite allergic inflammation and to protect against viruses without exacerbating airways hyperreactivity or mucous metaplasia. However, the deeply entrenched position that all inflammation is harmful to asthma patients demands that the mechanisms of the antiviral response be clarified, in order to promote the clinical translation of this paradigm-challenging strategy. In addition to quantifying the efficacy of this strategy for preventing virus-induced asthma in mice, this application proposes to reveal the mechanisms of antiviral resistance using genetic, pharmacologic and in vitro tools. First, the specific epithelia cell populations required for protection will be identified, facilitating subsequent mechanistic investigations and optimizing clinical delivery of inhaled therapies. Second, the proximal signaling molecules required to induce antiviral protection will be identified, allowing dissection of previously undescribed synergistic signaling events and identifying alternate druggable targets for inducing protection. Finally, the signaling cascade will be followed to the ultimate antiviral effector molecules. Recent experimental data and literature suggest that the virucidal moieties may be reactive oxygen or nitrogen species. So, novel mechanisms of volatile antiviral molecules will be specifically investigated. This project challenges prevailing concepts regarding the nature of inflammation in antimicrobial responses, the role of protective immunity in asthma, the cells required for antiviral host responses, cardinal concepts of coordinate signal transduction, the character of virucidal molecules and the source of lung free radicals. Together, these data are expected to promote clinical translation of a new era of asthma therapy.

描述（由申请人提供）：越来越多的美国人患有控制不佳的哮喘。由于嗜酸性粒细胞和中性粒细胞炎症是疾病的标志，因此抗炎药物是主要的治疗方法，尽管它们不能延缓疾病进展。病毒感染会导致大多数病情恶化并导致哮喘进展，但并未成为哮喘指南的目标。相反，免疫抑制疗法会增强病毒的易感性。肺上皮细胞是大多数呼吸道病毒的主要目标，对哮喘发病机制至关重要，并且是呼吸道病毒清除所必需的。最近的研究表明，可以通过治疗刺激肺上皮细胞，以广泛预防包括病毒感染在内的致死性肺炎。因此，推测在肺部引发保护性局部抗病毒免疫反应，而不是不加区别地抑制所有炎症，将预防哮喘恶化并减少进展。尽管有过敏性炎症，但对病毒的诱导性抵抗已被证明持续存在，并且可以在不加剧气道高反应性或粘膜化生的情况下抵御病毒。然而，所有炎症都对哮喘患者有害的根深蒂固的立场要求阐明抗病毒反应的机制，以促进这一挑战范式策略的临床转化。除了量化该策略预防小鼠病毒诱发哮喘的功效外，该应用还提出利用遗传、药理学和体外工具揭示抗病毒耐药机制。首先，将确定保护所需的特定上皮细胞群，以促进后续的机制研究并优化吸入疗法的临床实施。其次，将鉴定诱导抗病毒保护所需的近端信号分子，从而允许解剖以前未描述的协同信号传导事件并确定用于诱导保护的替代药物靶点。最后，信号级联将产生最终的抗病毒效应分子。最近的实验数据和文献表明，杀病毒部分可能是活性氧或氮物种。因此，将专门研究挥发性抗病毒分子的新机制。该项目挑战了有关抗菌反应中炎症的性质、哮喘中保护性免疫的作用、抗病毒宿主反应所需的细胞、协调信号转导的基本概念、杀病毒分子的特征和肺自由基的来源等流行概念。这些数据有望共同促进哮喘治疗新时代的临床转化。