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

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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.