Investigating the physiological and biochemical role of SOCS5 in the immune system

哮喘影响着全世界数百万人，是一种复杂的肺部炎症性疾病。哮喘表现为反复发作的喘息、呼吸困难、胸闷和咳嗽。三种关键蛋白质叫做；白细胞介素4 （IL-4）、白细胞介素13 （IL-13）和白细胞介素5 （IL-5）是由白细胞的一个亚群（T辅助细胞；Th2）产生的，被认为是哮喘反应的原因。正常情况下，这些蛋白质的作用是协调机体对寄生虫感染的免疫防御。换句话说，哮喘被认为是在没有寄生虫感染的情况下，通过不适当的IL-4和IL-13活性而引起的。额外的IL-13通常存在于哮喘患者的肺部，被认为有助于引发哮喘发作。IL-13是可用于治疗哮喘的药物的有效靶点。SOCS基因是在我们的实验室发现的，通过在小鼠中基因删除，我们证明了SOCS1， SOCS2和SOCS3在调节免疫反应和生长激素的作用中起关键作用。我的假设是，SOCS5是哮喘反应的重要生理调节因子。本研究将探讨IL-4和IL-13作用调控的基本生化过程及其与哮喘和免疫疾病发展的关系。我计划在缺乏SOCS4和SOCS5基因的小鼠中诱导哮喘发作。如果在缺乏这些蛋白的情况下，攻击的严重程度更大，这将表明SOCS4和或SOCS5是IL-4和IL-13的重要负调节因子。这有可能为开发可用于预防和治疗哮喘的药物开辟一个全新的策略。

Asthma affects millions of people worldwide and is a complex inflammatory disease of the lung. Asthma manifests as recurrent episodes of wheezing, breathlessness, chest tightening, and coughing. Three key proteins called; interleukin 4 (IL-4), interleukin 13 (IL-13) and interleukin 5 (IL-5) are produced by a subset of white blood cells (T helper cells; Th2) and are thought to be responsible for the asthma response. Normally these proteins act to coordinate the body s immune defence against parasite infection. In other words, asthma is thought to arise through inappropriate IL-4 and IL-13 activity in the absence of a parasite infection. Extra IL-13 is commonly found in the lungs of asthmatics and is thought to help trigger asthma attacks. IL-13 is a validated target for drugs that could be used in the treatment of asthma. The SOCS genes were discovered in our laboratory and by genetically deleting the genes in mice we have demonstrated a critical role for SOCS1, SOCS2 and SOCS3 in regulating the immune response and the action of growth hormone. My hypothesis is that SOCS5 is an important physiologic regulator of the asthma response. This proposal will investigate the basic biochemical processes underlying the regulation of IL-4 and IL-13 action and the relationship to development of asthma and immune disease. I plan to induce asthma attacks in mice that lack the genes for SOCS4 and SOCS5. If the severity of the attacks is greater in the absence of these proteins this will indicate that SOCS4 and-or SOCS5 are important negative regulators of IL-4 and IL-13. This has the potential to open up a completely new strategy for the development of drugs that could be used in the prevention and treatment of asthma.