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，这是巨大的医疗支出的原因。药物（如皮质类固醇）有助于控制哮喘症状和哮喘恶化，但停药后其作用迅速消失。因此，迫切需要研究哮喘发生、发展的致病机制和调控机制，以更好地了解哮喘的控制和加重，为哮喘的防治提供新的契机。非甾体抗炎药（NSAID，如阿司匹林）在世界范围内作为止痛药和退烧药大量使用。这是因为这些药物阻断了一组称为前列腺素（PGs）的脂质的产生，这些脂质介导了疼痛反应和发热。然而，与其他药物一样，NSAID也会引起不良反应-例如，最著名的一种是引起肠道出血。我们的研究小组最近发现了一种以前未知的机制，即为什么使用NSAID会导致肠道出血，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，对于野牡丹素如何在加重刺激（例如过敏原或病原体诱导的过敏性炎症）中发挥作用还没有很好的了解。临床和流行病学观察表明，使用NSAID可引发哮喘和肺部炎症的加重，如重度慢性嗜酸性鼻窦炎伴鼻息肉病，这种疾病称为NSAID加重的呼吸道疾病（NERD）。我在这个应用程序中的目标是发现哮喘是如何发展和加剧的过敏物质或药物的刺激，以及如何控制这些过敏的化学反应，治疗哮喘和NERD的科学事实。一个亚群的免疫细胞称为2型先天淋巴样细胞（ILC 2）最近已被证明介导的发展和哮喘患者在动物模型和哮喘的恶化。但是在哮喘的背景下负控制ILC 2功能的信号仍有待揭示。在这个CDA应用中，我将使用药理学，免疫学和遗传学方法以及实验模型和通过分析哮喘患者的临床样本来定义野牡丹素在保护免受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。这种连贯的实验组合将有助于剖析患者生理前列腺素信号传导功能障碍导致哮喘和NERD发展的特定致病机制。在这种情况下，前列腺素信号的成功验证将为相关过敏性肺部炎症的治疗提供新的治疗选择。

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.