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抵抗病原体，这些方式大致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，与适应性免疫相比，先天免疫具有高度的进化保守性，可以由我们体内许多非主要免疫细胞类型的细胞发挥作用。功能性先天免疫反应对生命至关重要。先天免疫的失败导致病原体驱动的疾病和它的解除管制慢性炎症条件。先天免疫的关键是对一系列基因的适当调节。这种调节在很大程度上是由包含这些基因的DNA如何在细胞内被大量蛋白质包装成一种称为染色质的上层结构所介导的。然而，关于“染色质重塑”如何支持功能性先天免疫反应的知识是有限的。在我们（Patrick Varga-Weisz）对小鼠的研究中，我们发现一种名为Smarcad1的染色质重塑蛋白是肠道先天免疫反应的关键组成部分。然而，使用小鼠模型来进一步阐明这一点是非常昂贵的，缓慢的，并且涉及到这些动物的侵入性手术。果蝇在发现先天免疫的分子过程中发挥了重要作用，朱尔斯·a·霍夫曼（Jules A. Hoffmann）因此获得2011年诺贝尔奖。在这项提议中，我们希望将多米尼克·费兰登博士（斯特拉斯堡molsamculare和Cellulaire生物研究所）实验室在苍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。多米尼克是这一领域的主要研究人员，曾在朱尔斯·a·霍夫曼的实验室接受过培训，并建立了研究这一重要生物学问题的复杂方法。使用Ferrandon博士的方法，我们可以利用果蝇强大的遗传学来揭示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对抗感染和病理性炎症的药理学调节提供靶点。与此同时，来自果蝇的这些结果将导致在这些研究中直接取代小鼠，也可能在Varga-Weisz博士的巴西合作者网络中直接取代小鼠。

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.