Acquisition of the Drosophila model system to understand mechanisms of innate immunity regulation by chromatin dynamics

点击翻译按钮获取中文摘要

Our body fights off pathogens in multiple ways, which are broadly summarised as innate and adaptive immunity. Innate immunity comprises an array of cellular responses against pathogens that, by contrast to the adaptive immunity, is highly evolutionarily conserved and can be enacted by many cell types in our body that are not primarily immune cells. A functional innate immunity response is essential for life. Failure of innate immunity leads to pathogen-driven diseases and its deregulation to chronic inflammatory conditions.Critical to innate immunity is the proper regulation of a cascade of genes. This regulation is largely mediated by how the DNA that contains those genes is packaged within cells by a plethora of proteins into a superstructure called chromatin. However, the knowledge of how 'chromatin remodelling' supports a functional innate immunity response is limited. In our research (Patrick Varga-Weisz), using mice, we have implicated a chromatin remodelling protein called Smarcad1 as a critical component in the innate immunity response in the gut. However, to elucidate this further using the mouse model is very expensive, slow and involves invasive procedures in these animals.The fruit fly Drosophila melanogaster has been instrumental in the discovery of molecular processes of innate immunity, leading to the 2011 Nobel prize to Jules A. Hoffmann.In this proposal, we wish to transfer world-class expertise in fly innate immunity from the lab of Dr Dominique Ferrandon (Institute de Biologie Moléculare et Cellulaire, Strasbourg) to our labs at the University of Essex. Dominique is a leading researcher in this field, having been trained in the lab of Jules A. Hoffmann and having established sophisticated approaches to study this important biological problem.Using the methods from Dr Ferrandon, we can employ the powerful genetics of Drosophila to unravel details of how chromatin remodelling regulates innate immunity. These insights may provide targets for the pharmacological regulation of innate immunity to fight infections and during pathological inflammatory conditions. Meanwhile, these results from Drosophila will lead to the direct replacement of mice in these studies locally as well as potentially in the Brazilian network of collaborators of Dr Varga-Weisz.