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

我们的身体以多种方式对抗病原体，这些方式被概括为先天免疫和适应性免疫。先天免疫包括一系列针对病原体的细胞反应，与适应性免疫相反，其在进化上高度保守，并且可以由我们体内的许多细胞类型（主要不是免疫细胞）产生。功能性先天免疫反应对生命至关重要。先天免疫的失败会导致病原体驱动的疾病及其失调，从而导致慢性炎症。先天免疫的关键是对级联基因的适当调节。这种调节在很大程度上是由包含这些基因的DNA如何在细胞内被过多的蛋白质包装成称为染色质的超结构来介导的。然而，关于“染色质重塑”如何支持功能性先天免疫应答的知识是有限的。在我们的研究中（帕特里克瓦尔加-韦兹），使用小鼠，我们已经暗示了一种名为Smarcad 1的染色质重塑蛋白是肠道先天免疫反应的关键成分。然而，使用小鼠模型来进一步阐明这一点是非常昂贵、缓慢的，并且涉及这些动物中的侵入性程序。果蝇黑腹果蝇在发现先天免疫的分子过程中发挥了重要作用，导致2011年诺贝尔奖授予朱尔斯A。在本提案中，我们希望将Dominique Ferrandon博士实验室（分子和细胞生物学研究所，斯特拉斯堡）在果蝇先天免疫方面的世界级专业知识转移到我们在埃塞克斯大学的实验室。Dominique是这一领域的主要研究人员，曾在Jules A. Hoffmann和已经建立了复杂的方法来研究这个重要的生物学问题。使用Ferrandon博士的方法，我们可以利用果蝇强大的遗传学来解开染色质重塑如何调节先天免疫的细节。这些见解可能为先天免疫的药理学调节提供靶点，以对抗感染和病理炎症条件。与此同时，果蝇的这些结果将导致在这些研究中直接取代小鼠，并可能在Varga-Weisz博士的巴西合作者网络中取代小鼠。

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.