MRC-GSK Alliance: Mechanisms of interplay between allergy and viruses in asthma

我们申请在葛兰素史克和MRC&哮喘英国中心之间建立哮喘过敏机制联盟，以发现和开发预防/治疗哮喘和哮喘发作的新方法。我们将把该中心主要优势领域的研究与葛兰素史克在哮喘药物发现方面的优势结合起来。总体目标是研究过敏和病毒感染在哮喘发展和急性哮喘发作中的相互作用机制。哮喘发作的主要原因是人类鼻病毒(RV)感染，这些感染也与哮喘的发生有关，当它们发生在生命的早期。我们将研究RV感染过程中肺细胞的基因表达和表达如何调节，以确定RV感染诱导的与促进过敏反应有关的分子/途径，我们将确定这些分子/过程的RV诱导/修饰是否与先前存在的过敏反应、病毒载量和哮喘加重的临床严重程度有关。哮喘的一个主要原因是未能形成对变应原的免疫耐受性。我们已经证明，耐受性可以被病毒感染逆转，但机制尚不清楚。我们将从病毒诱导的耐受性崩溃模型中提纯肺细胞，以确定与耐受性崩溃有关的基因，并确定这些基因是否在人类肺细胞中复制。最后，我们将确定是否阻断或诱导与病毒诱导的过敏反应恶化/耐受性崩溃有关的分子，确定RV诱导的过敏性呼吸道炎症的严重程度。这些目标的完成将为哮喘和哮喘发作的新疗法的开发确定靶点。

We apply to form an Alliance between GSK and the MRC & Asthma UK Centre in Allergic Mechanisms of Asthma to discover and develop new approaches for prevention/treatment of asthma and asthma attacks. We will integrate research in areas of major strength for the Centre with the strengths in asthma drug discovery at GSK. The overall aim is to investigate mechanisms of interplay between allergy and virus infection in development of asthma and in acute asthma attacks. The major cause of asthma attacks are human rhinovirus (RV) infections, these are also related to development of asthma when they occur in early life. We will investigate gene expression and how expression is regulated in lung cells during RV infection to identify molecules/pathways induced by RV infection that are implicated in promoting allergic responses.We will determine whether RV induction/modification of these molecules/processes are related to pre-existing allergic responses, virus load and clinical severity of asthma exacerbation. A major cause of asthma is failure of development of immunological tolerance to allergens. We have shown that tolerance can be reversed by a virus infection, but the mechanisms are unknown. We will purify lung cells from the virus-induced breakdown of tolerance model to identify genes implicated in tolerance breakdown and determine whether these are replicated in lung cells in the human.Finally we will determine whether blocking or inducing molecules implicated in virus induced worsening of allergic responses/breakdown of tolerance, determines severity of RV induced allergic airway inflammation.Accomplishment of these aims will identify targets for development of novel therapies for asthma and asthma attacks.