Is Lyn tyrosine kinase a predictor of severe, persistent multi-trait asthma and allergy?

哮喘是澳大利亚的一个主要健康问题，在任何时候都影响着超过10%的人口，超过25%的人口在他们生命的一个阶段。虽然公众认为哮喘治疗改善了疾病的管理，但每年有700多人死于严重哮喘，在澳大利亚和大多数发达国家，因病情恶化（突然恶化）而住院治疗是医疗负担中最昂贵的组成部分之一。目前还没有分子标记可以预测谁会患上严重哮喘，也没有特定的治疗方法来逆转严重的恶化。这个项目将使用先进的分子生物学方法来检验一种叫做Lyn的分子是否重要。Lyn酪氨酸激酶是参与跨细胞膜传递信息的基因家族的一员。这种酶在血细胞中表达，参与感染、免疫和过敏反应的机制。为了进一步了解这种酶在整个动物环境中的作用，我们产生了无法产生Lyn蛋白的小鼠（Lyn缺陷小鼠）。在哮喘的动物模型中，我们知道如果Lyn不起作用，就会出现严重和持续的哮喘。我们也做了初步的研究，表明Lyn对那些因威胁生命的哮喘而被送进急诊室的人不起作用。在这项研究中，我们将详细研究Lyn在哮喘和过敏中所起的作用，我们打算确定导致Lyn缺陷小鼠哮喘的途径。我们还将研究我们的假设，即哮喘和过敏患者的Lyn活性可能减少或失调。这项研究将为严重哮喘提供更好的预测指标，并改进和特异性治疗。

Asthma is a major health problem in Australia affecting over 10% of the population at any time, and more than 25% of the population at one stage in their lives. Although the public perception is that asthma treatments have improved management of the disease, more than 700 people die from severe asthma each year and hospitalisation from exacerbation (sudden worsening) is one of the most costly components of the health care burden in Australia and most developed countries. Currently there are no molecular markers that can predict who will get severe asthma and there are no specific treatments to reverse severe exacerbations. This project will use advanced molecular biology methods to examine whether a molecule called Lyn may be important. The Lyn tyrosine kinase is a member of a family of genes that participate in transmitting information across the cell membrane. This enzyme is expressed in blood cells, and is involved in mechanisms pertaining to infection, immunity and allergic responses. To further our understanding of the role of this enzyme in the context of the whole animal, we have generated mice that are unable to make Lyn protein (Lyn-deficient mice). In animal models of asthma we know that if Lyn is not functioning, severe and persistent asthma develops. We have also made preliminary studies that suggest that Lyn does not work properly in people who have been admitted to the emergency ward with life threatenting asthma. In this study we will examine in detail the role that Lyn plays in asthma and allergy, and we intend to identify the pathways that give rise to asthma in Lyn-deficient mice. We will also investigate our hypothesis that Lyn activity may be reduced or disregulated in patients with asthma and allergy. This research should lead to better predictive markers for severe asthma and also to improved and specific treatments.