To delineate immune mechanisms for limiting asthma development and severity

全世界有超过3亿人患有哮喘，每年导致25万人死亡，这是巨额医疗支出的原因。药物（如皮质类固醇）有助于控制哮喘症状和哮喘加重，但一旦停用，其效果就会迅速消失。因此，迫切需要研究哮喘发生、加重的致病机制和调控机制，以更好地了解哮喘及其加重的控制，从而为哮喘的防治提供新的机遇。非甾体抗炎药（非甾体抗炎药，如阿司匹林）在世界范围内被广泛用作止痛药和退烧药。这是因为这些药物阻断了一组被称为前列腺素（pg）的脂质的产生，这种脂质介导疼痛反应和发烧的产生。然而，像其他药物一样，非甾体抗炎药也会引起副作用——例如，最著名的是诱发肠道出血。我们的团队最近发现了一个以前未知的机制，为什么使用非甾体抗炎药导致肠道出血，并发现脂质介质前列腺素E2在维持肠道屏障稳态中的重要作用。但是前列腺素如何对加重的刺激（如过敏原或病原体引起的过敏性炎症）起作用尚不清楚。临床和流行病学观察表明，使用非甾体抗炎药会引发哮喘和肺部炎症的恶化，如严重的慢性嗜酸性鼻窦炎伴鼻息肉病，这种情况被称为非甾体抗炎药加重呼吸系统疾病（NERD）。我在这个申请中的目标是发现哮喘是如何在过敏物质或药物的刺激下发展和加剧的科学事实，以及如何控制这些过敏化学反应来治疗哮喘和NERD。一种被称为2型先天淋巴样细胞（ILC2s）的免疫细胞亚群最近被证明在动物模型和哮喘患者中介导哮喘的发生和加重。但在哮喘的情况下，抑制ILC2功能的信号仍有待揭示。在这个CDA应用中，我将通过药理学、免疫学和遗传学方法，以及实验模型和哮喘患者临床样本的分析，定义前列腺素在预防2型过敏性肺部炎症中的作用，以及精确的细胞和分子机制。这一连贯的实验组合将有助于剖析哮喘和NERD通过患者生理前列腺素信号功能障碍发展的具体致病机制。在这种情况下，前列腺素信号传导的成功验证将为治疗相关的过敏性肺部炎症提供新的治疗选择。

There are more than 300 million people worldwide living with asthma, and it causes 250,000 deaths annually, which is responsible for huge healthcare expenditure. Drugs (e.g. corticosteroids) help control both asthma symptoms and asthma exacerbations, yet their effects rapidly disappear when discontinued. It is thus urgent to study the pathogenic mechanisms underlying the development and exacerbation of asthma and the regulatory mechanisms for better understanding of the control of asthma and its exacerbation, which will help for providing new opportunities to prevention and treatment of asthma. Non-steroidal anti-inflammatory drugs (NSAIDs such as aspirin) are very commonly used at huge amounts as pain killers and reducing fever worldwide. This is because these drugs block the production of a group of lipids called prostaglandins (PGs) that mediate the pain response and fever generation. Like other drugs, however, NSAIDs can also cause adverse effects - e.g., the most well known one is inducing gut bleeding. Our group has recently discovered a previously unknown mechanism as to why use of NSAIDs leads to bleeding in the gut and found an essential role of the lipid mediator prostaglandin E2 in the maintenance of gut barrier homeostasis. But how prostaglandins function in response to aggravating stimuli (e.g. allergen- or pathogen-induced allergic inflammation) are not well understood. Clinical and epidemiological observations suggest that use of NSAIDs triggers exacerbations of asthma and lung inflammation such as severe chronic eosinophilic rhinosinusitis with nasal polyposis, a condition called as NSAID-exacerbated respiratory disease (NERD). My goal in this application is to discover the scientific facts as to how asthma is developed and exacerbated by stimuli of allergic substances or drugs and how to control these allergic chemical reactions for treatment of asthma and NERD.A subset of immune cells called type 2 innate lymphoid cells (ILC2s) has recently been demonstrated to mediate the development and exacerbation of asthma in both animal models and patients with asthma. But signals that negatively control ILC2 function in the context of asthma remain to be revealed. In this CDA application, I will define the role of prostaglandins in protection against type 2 allergic lung inflammation and the precise cellular and molecular mechanisms using pharmacological, immunological and genetic approaches, as well as experimental models and via analysis of clinical samples from asthma patients. This coherent portfolio of experiments will help dissect the specific pathogenic mechanisms for the development of asthma and NERD by dysfunction of the physiological prostaglandin signalling in patients. Successful validation of prostaglandin signalling in this context will provide new therapeutic options for the treatment of related allergic lung inflammation.