MicroRNAs and their epigenetic regulation as key factors in airway macrophage dysfunction in asthma.

哮喘影响全世界2.35亿人（根据世卫组织的估计），对所有国家的卫生经济造成巨大负担。这种疾病的特点是气流阻塞，随着时间的推移，往往变得不可逆转。不可逆性是气道重塑和纤维化的结果，与治疗耐药性和通常由病毒感染引起的急性加重的易感性有关。哮喘恶化是一个主要的未满足的需求，估计在英国造成12亿英镑的生产力损失，8.5亿英镑的NHS医疗保健费用和1.61亿英镑的社会保障费用。因此，了解疾病加重易感性增加的基础是哮喘管理的首要需要，特别是当人们意识到2005年英国有1,300多人死于哮喘（1,318人）（27人是14岁或以下的儿童）。现在认识到，哮喘患者气道巨噬细胞可能不太能够处理病毒和细菌感染。这些细胞构成了抵御病原体、毒素和其他环境损害的第一道防线，因此对气道对环境的反应至关重要。在本提案中，我们打算确定一个新的短RNA分子家族，即microRNAs的作用，它们已被证明参与发育、疾病和许多生物过程。我们发现，在哮喘中，这些microrna是失调的，导致肺免疫系统功能的不平衡。我们的初步结果表明，当哮喘患者气道变应性炎症增强时，这种放松管制的作用更加明显。在这些情况下的变化是那些会使哮喘患者更容易受损的病毒反应，从而增加哮喘恶化的可能性。这与我们最初的发现“一致”，即在巨噬细胞中，microrna的失调似乎是减少保护性干扰素- β (ifn - β)分泌、增加tnf - α（一种强效的促炎细胞因子）的过度表达、降低巨噬细胞的病原体结合能力从而降低其处理病原体的能力的重要因素。我们打算证明哮喘巨噬细胞在这三个关键功能上存在缺陷，并且环境因素，如病毒感染和过敏原挑战，进一步降低了它们适当处理病原体的能力。microrna相对容易用合成的寡核苷酸操纵。因此，它们是一个很好的治疗靶点，可以帮助减少哮喘恶化和哮喘患者的负担。最后，我们将研究哮喘巨噬细胞中microrna和受其影响的基因失调的原因。我们有初步证据表明，哮喘巨噬细胞中的microRNAs表达可能受到差异表观遗传控制的影响。表观遗传控制是基因表达长期和持续调控的重要机制，可能解释哮喘发病和进展过程中与哮喘相关的几个基因的失调。因此，环境因素可以产生重要的表观遗传，从而影响肺中巨噬细胞的功能。因此，我们将研究环境或内在因素是否会影响关键免疫功能的表观遗传控制，这些功能可能在生命过程中倾向于进展为更严重的哮喘表型。因此，拟议的研究将解决与哮喘控制和疾病恶化相关的重要问题，并具有重要的潜力，可以确定现实的治疗靶点，并为这种复杂气道疾病的发病和进展提供见解。

Asthma affects 235 million people worldwide (according to WHO estimates) and is a great burden on the health economies of all nations. The disease is characterised by airflow obstruction that, over time, tends to become irreversible. The irreversibility, a consequence of airway remodelling and fibrosis, is associated both with treatment resistance and susceptibility to acute exacerbations usually induced by viral infections. Asthma exacerbations are a major unmet need and are estimated to cost £1.2 billion in lost productivity, £850 million in NHS health care provision and a further £161 million in social security costs within the UK. Understanding the basis for the increased susceptibility to disease exacerbation thus represents the primary need in asthma management especially when it is appreciated that there were just over 1,300 deaths (1,318) from asthma in the UK in 2005 (27 were children aged 14 years or under).It is now appreciated that airway macrophages from asthmatics may be less able to deal with viral and bacterial infections. These cells form the first line of defence against pathogens, toxins and other environmental insults and hence, are critical to the airway response to the environment.In this proposal we intend to determine the role of a novel family of short RNA molecules, microRNAs, which have been shown to participate in development, disease and many biological processes. We have found that, in asthma, these microRNAs are dysregulated, causing an imbalance in the functions of the immune system of the lung. Our preliminary results indicate that this deregulation is even more apparent when asthmatics have enhanced allergic inflammation with in the airways. The changes under these circumstances are those that would make asthmatics more prone to impaired viral responses and thus increase the likelihood of an asthmatic exacerbations. This "ties in" with our initial findings that, in macrophages, the deregulation in microRNAs seems to be an important factor in decreasing the secretion of protective interferon-beta (IFN-beta), increasing the over-expression of TNF-alpha, a potent pro-inflammatory cytokine, and reducing the pathogen binding ability of macrophages and thus their capacity to deal with pathogens. We intend to demonstrate that asthmatic macrophages show a deficiency in these three key functions and that environmental factors, such as viral infection and allergen challenge, further decrease their ability to appropriately deal with pathogens. MicroRNAs are relatively easy to manipulate with synthetic oligonucleotides. Thus, they make a good therapeutic target that could help reduce asthmatic exacerbations and the burden on asthma sufferers.Finally, we will investigate the causes for this dysregulation in asthmatic macrophages both in microRNAs and the genes affected by them. We have preliminary evidence showing that microRNAs expression might be affected by a differential epigenetic control in asthmatic macrophages. Epigenetic control is an important mechanism for long-term and sustained regulation of gene expression and might explain the dysregulation of several genes associated with asthma in the onset and progression of the disease. Environmental factors can thus produce important epigenetic that will affect the functionality of macrophages in the lung. We will therefore study whether environmental or intrinsic factors affect the epigenetic control of crucial immune functions that may predispose to progression into a more severe asthmatic phenotype during life course.The proposed study will thus address important issues relevant to asthma control and disease exacerbation and has significant potential to lead to the identification of realistic therapeutic targets as well as providing insight into the onset and progression of disease in this complex airway disorder.