Interplay between the Endocrine and Innate Systems of Drosphila

描述（由申请人提供）：先天免疫是一种古老的防御反应，与最早的后生动物一起进化，是抵御微生物感染的第一道防线。这些反应依赖于生殖细胞编码的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。面对不断的微生物攻击，先天免疫对几乎所有生物的生存至关重要。 多细胞生物另一方面，过度旺盛或不适当的先天免疫应答是与许多感染性和自身免疫性疾病相关的发病率和死亡率的根本原因。内分泌系统，通过类固醇以及性激素和维生素D，对先天免疫反应具有深刻的促炎或抗炎作用。这种先天免疫系统和内分泌系统之间的相互作用在整个动物王国中都有发现，并且可能与一些最早的动物一起进化。该建议使用果蝇Drosophila melanogaster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，包括实验易处理性，可以说是体内研究中最强大的遗传系统，类固醇激素调节网络的广泛知识，以及先天免疫系统没有适应性免疫反应的复杂性。此外，果蝇的免疫反应是病媒昆虫物种的一个很好的模型，在果蝇中的发现正在转化为控制病媒传播疾病的新方法。此外，先天免疫反应的许多方面在哺乳动物中是高度保守的，并且在苍蝇中的发现可以转化为哺乳动物中的范式转变发现。与本建议特别相关的是 NF-κB信号通路，其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，类固醇信号在果蝇和哺乳动物之间高度保守。 一个彻底的机制分析先天免疫反应是如何调节类固醇激素在果蝇模型系统将提供更深入的了解这些古老的监管相互作用，并有可能确定新的途径来操纵这些相互作用的载体昆虫和/或哺乳动物。初步数据表明，昆虫类固醇激素20-羟基蜕皮激素（蜕皮激素）对NF-κB依赖性先天免疫应答具有显著的增强作用。蜕皮激素似乎通过至少两种机制调节果蝇先天性反应，通过控制关键先天免疫受体的表达和通过调节特异性靶基因的诱导。这些结果表明，这种类固醇激素的功能是在发育过程中塑造免疫反应，以及在压力时期引发更有效的反应。目的1和2旨在阐明这种免疫激素控制的分子机制，并探索其潜在功能。在目标3中，我们将测试一种新的替代假设，即类固醇调节的免疫信号传导和抗菌肽（AMP）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-κB 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-κB 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.