Genetic dissection of the function of the Src family tyrosine kinase Hck in inflammatory lung disease

该项目旨在确定更好和更安全的治疗严重的、危及生命的炎症性肺病的方法，如慢性阻塞性肺病（COPD），它影响着全世界6亿多人，是澳大利亚的一个主要健康问题。目前还没有有效的治疗方法可以逆转或减缓这些疾病。这项研究是基于我们最近的发现，一种叫做Hck的酶可能在肺部疾病中起着非常重要的作用。我们使用了一种遗传方法将Hck转化为活性形式的小鼠。这些小鼠出生时看起来很正常，但后来出现了类似于人类严重肺部疾病的进行性肺部炎症。令人惊讶的是，小鼠也表现出对细菌感染肺部物质的增强反应——一种所谓的先天免疫反应。这使我们得出结论，小鼠的主要问题实际上是增强的先天免疫——通常是保护性的——转而对抗肺部导致疾病。为了准确理解是什么控制着保护和肺损伤之间的这种微妙平衡，我们将使用新的和复杂的基因修饰方法，使我们能够将Hck活性的变化靶向到我们怀疑是该疾病主要原因的特定细胞上。在这样做的过程中，我们将在这些细胞中添加特殊的标签，这样我们就可以分离出疾病过程中的控制分子。我们对一种叫做巨噬细胞的细胞特别感兴趣，巨噬细胞是肺部的一种主要防御细胞，也被认为能够引起肺部疾病。我们的目标是找到控制疾病的分子，这些分子可以被新药阻断，这些新药既可以抑制疾病，又可以防止肺部感染。

This project aims to identify better and safer treatments for serious, life-threatening inflammatory lung diseases, such as Chronic Obstructive Lung Disease (COPD), which affect over 600 million people worldwide and are a major health problem in Australia. There are no effective treatments that can reverse or slow these diseases. The research is based on our recent discovery that an enzyme called Hck might play a very important role in lung disease. We used mice in which a genetic method had been used to change Hck into its active form. The mice appeared normal when they were born but developed a progressive lung inflammation that resembled serious human lung diseases. Surprisingly, the mice also displayed enhanced responses to substances from bacteria that can infect the lung - a so-called innate immune response. This led us to conclude that the main problem in the mice was actually enhanced innate immunity - which is usually protective - turning against the lung to cause disease. To understand exactly what controls this fine balance between protection and lung damage, we will use new and sophisticated gene modification methods that allow us to target changes in Hck activity to specific cells that we suspect are the main cause of the disease. In doing so we will add special tags into these cells, so that we can isolate the controlling molecules in the disease process. We are particularly interested in a cell called the macrophage, a major defensive cell in the lung that is also known to be capable of causing lung disease. Our aim is to find disease-controlling molecules that could be blocked with new drugs that would suppress disease but spare defenses against lung infections.