Interplay between the Endocrine and Innate Systems of Drosphila

项目摘要/摘要 先天免疫是一种古老的防御反应，它与最早的后生动物一起进化而来，是 抵御微生物感染的第一道防线。这些反应依赖于微生物的识别 生殖线编码的受体，并驱动大量化学、生物和细胞防御的产生 回应。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 与许多传染病和自身免疫性疾病相关的发病和死亡的根本原因。这个 内分泌系统，通过类固醇以及性激素和维生素D，具有深刻的促进或反对 炎症对先天免疫反应的影响。这种先天免疫和内分泌之间的串扰 系统在动物界随处可见，很可能是与一些最早的动物一起进化的。这 Proposal使用果蝇作为研究这些相互作用的模型。苍蝇提供 这些研究的许多优点，包括可以说是最健壮的基因的实验可控性 体内研究系统，类固醇激素调节网络的广泛知识，以及先天免疫 系统没有复杂的适应性免疫反应。此外，先天的许多方面 哺乳动物的免疫反应是高度保守的，在苍蝇身上的发现可以转化为 哺乳动物的范式转换发现。与这一提议特别相关的是保守的NF-κB 驱动对感染的即时反应的信号通路以及这些信号的调节 类固醇激素的作用途径。 类固醇激素如何调节先天免疫反应的全面机制分析 果蝇模型系统将提供对这些古老的调控相互作用的更深层次的理解，以及 很可能确定在媒介昆虫和/或哺乳动物中操纵这些相互作用的新途径。 初步数据表明，昆虫类固醇激素20-羟基蜕皮酮具有显著的促进作用 通过调节细菌的表达对NF-κB依赖的先天免疫反应的影响 传感受体PGRP-LC。这个调节网络使蜕皮激素能够启动先天免疫。 反应，在压力时期创造更有效的免疫防御。目标1中概述的实验是 旨在阐明这种荷尔蒙控制免疫的分子机制，而Aim 2将 探讨类固醇蜕皮激素对应激和启动反应的分子和细胞机制 免疫防御。在目标3中，我们将探讨类固醇调节的免疫信号在驾驶中的作用 发育程序性自噬细胞死亡和组织降解。所有这三个目标都建立在 并以令人兴奋的新方向扩展我们对这笔赠款的前一轮支持的结果。

Project Summary/Abstract 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. 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 pathways, which drive the immediate response to infection, and the modulation of these signaling pathways by steroid hormones. 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 has a profound enhancing effect on NF-κB dependent innate immune responses, through regulating the expression of the bacterial sensing receptor PGRP-LC. This regulatory network enables the ecdysone to prime the innate immune response, creating more effective immune defenses in times of stress. The experiments outlined in Aim 1 are designed to elucidate the molecular mechanisms underlying this hormonal control of immunity, while Aim 2 will probe the molecular and cellular mechanisms by which the steroid ecdysone responds to stress and primes immune defenses. In Aim 3, we will probe the role steroid-regulated immune signaling in driving developmentally programmed autophagic cell death and tissue degradation. All three of these Aims build upon, and extend in exciting new directions, the findings from our previous cycle of support for this grant.