Interplay between the Endocrine and Innate Systems of Drosphila

描述(申请人提供)：先天免疫是一种古老的防御反应，由最早的后生动物进化而来，是抵御微生物感染的第一道防线。这些反应依赖于生殖线编码受体对微生物的识别，并驱动许多化学、生物和细胞防御反应的产生。面对持续不断的微生物攻击，先天免疫对几乎所有生物的生存都至关重要。 多细胞生物。另一方面，过度活跃或不适当的先天免疫反应是许多感染性和自身免疫性疾病的发病率和死亡率的根本原因。内分泌系统通过类固醇、性激素和维生素D，对先天免疫反应有深刻的促炎或抗炎作用。这种先天免疫和内分泌系统之间的串扰在整个动物界都可以找到，很可能是随着一些最早的动物进化而来的。这项提议使用果蝇作为研究这些相互作用的模型。苍蝇为这些研究提供了许多优势，包括体内研究中最强大的遗传系统的实验可控性，类固醇激素调节网络的广泛知识，以及无需复杂的适应性免疫反应的先天免疫系统。此外，果蝇的免疫反应是媒介昆虫物种的一个很好的模型，在苍蝇身上的发现正在转化为控制媒介传播疾病的新方法。此外，哺乳动物天生免疫反应的许多方面都是高度保守的，在苍蝇上的发现可以转化为哺乳动物的范式转换发现。与这一建议特别相关的是保守的NF-？B信号通路，它驱动对感染的即时反应，以及类固醇激素对这些信号通路的调节。值得注意的是，类固醇信号在苍蝇和哺乳动物之间高度保守。对果蝇模型系统中类固醇激素如何调节先天免疫反应的彻底机制分析将有助于更深入地了解这些古老的调节相互作用，并可能找到在媒介昆虫和/或哺乳动物中操纵这些相互作用的新途径。初步研究表明，昆虫类固醇激素20-羟基蜕皮酮(简称蜕皮激素)对依赖于核因子？B的天然免疫反应有显著的增强作用。蜕皮激素似乎通过至少两种机制来调节果蝇的先天反应，通过控制关键的先天免疫受体的表达和通过调节特定靶基因的诱导。这些结果表明，这种类固醇激素在发育过程中起着塑造免疫反应的作用，并在压力时期启动更有效的反应。目标1和目标2旨在阐明荷尔蒙控制免疫的分子机制，并探索其潜在功能(S)。在目标3中，我们将测试一个新的替代假设，即类固醇调节的免疫信号和抗菌肽(AMPs)的产生促进发育细胞死亡。

DESCRIPTION (provided by applicant): Innate immunity is an ancient defense response that evolved with the earliest metazoan creatures, and is the first line of defense against microbial infection. These responses rely on the recognition of microbes by germline-encoded receptors, and drive the production of numerous chemical, biological, and cellular defense responses. In the face of constant microbial assault, innate immunity is essential for the survival of nearly all multicellular organisms. On the other hand, over-exuberant or inappropriate innate immune responses are the underlying cause of morbidity and mortality associated with many infectious and autoimmune diseases. The endocrine system, through steroids as well as sex hormones and vitamin D, has profound pro- or anti- inflammatory effects on the innate immune response. This crosstalk between the innate immune and endocrine systems is found throughout the animal kingdom, and likely evolved with some of the earliest animals. This proposal uses the fruit fly Drosophila melanogaster as a model for the study of these interactions. Flies offer many advantages for these studies, including experimental tractability with arguably the most robust genetic system for in vivo studies, extensive knowledge of steroid hormone regulatory networks, and an innate immune system without the complexity of the adaptive immune response. In addition, the Drosophila immune response is an excellent model for vector insect species, and discoveries made in flies are being translated into new approaches to control vector-borne diseases. Furthermore, many aspects of the innate immune responses are highly conserved with mammals, and discoveries made in flies can be translated into paradigm shifting findings in mammals. Particularly relevant for this proposal are the conserved NF-?B signaling pathway, which drives the immediate response to infection, and the modulation of these signaling pathways by steroid hormones. Significantly, steroid signaling is highly conserved between flies and mammals. A thorough mechanistic analysis of how the innate immune response is regulated by steroid hormones in the Drosophila model system will provide a deeper understanding of these ancient regulatory interactions, and are likely to identify new avenues for manipulating these interactions in vector insects and/or mammals. Preliminary data demonstrate that the insect steroid hormone 20-hydroxyecdysone (ecdysone) has a profound enhancing effect on NF-?B dependent innate immune responses. Ecdysone appears to modulate the Drosophila innate response by at least two mechanisms, by controlling expression of a key innate immune receptor and by regulating induction of specific target genes. These results suggest that this steroid hormone functions to sculpt immune responses during development as well as to prime more efficient responses during times of stress. Aims 1 & 2 are designed to elucidate the molecular mechanisms underlying this hormonal control of immunity as well as probe its underlying function(s). In Aim 3, we will test a novel alternative hypothesis that steroid-regulated immune signaling and antimicrobial peptides (AMPs) production facilitate developmental cell death.