Regulation of Host Signaling by Parasitoid Venom Proteins

寄生物毒蛋白对宿主信号传导的调节

• 批准号: 10204047
• 负责人: Nathan Terry Mortimer
• 金额: $ 23.43万
• 依托单位: ILLINOIS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204047
• 关键词: Bioinformatics; Biological Process; Cell physiology; Development; Disease; Dominant-Negative Mutation; Drosophila genus; Environment; Event; Goals; Health; Human; Immunologic Receptors; Infection; Invaded; Knowledge; Light; Link; MAPK8 gene; Modeling; Molecular; Organism; Parasites; Pathogenesis; Pathway interactions; Play; Proteins; Receptor Signaling; Regulation; Research; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Specificity; System; Tissues; Venoms; Virulence; Virulence Factors; Wasps; Work; biological systems; experimental study; human disease; human model; insight; novel; novel therapeutics; tool

The precise regulation of intra- and inter-cellular signaling events is crucial for the function of biological systems and plays an essential role in human health. Deregulated signaling can perturb cell function by altering the timing or strength of signal activity and can contribute to the pathogenesis of multiple diseases. Signal regulation is accomplished by a variety of intrinsic mechanisms, but signaling can also be manipulated by extrinsic factors including factors derived from other organisms or the environment. Interorganismal signal regulation is often observed during infection, in which a parasite can utilize virulence factors in order to alter host signaling events. In my lab we use the Drosophila-parasitoid wasp host-parasite system as a model to study the mechanisms used by parasites to manipulate host signaling. These parasitoids contain virulence proteins in their venoms, and work from my lab has demonstrated that parasitoid venom proteins can modify conserved signaling mechanisms including signal transduction pathways and second messenger systems in their hosts. Understanding the mechanistic basis of these venom protein activities will provide a powerful tool to study the regulation of signaling events, and will allow us to gain novel insight into conserved signaling mechanisms in Drosophila, an important model of human health. The objective of our research is to leverage this system to uncover novel mechanisms underlying signal regulation and to achieve these goals, research in my lab will focus on: 1) Identifying the molecular mechanisms used by parasitoid wasps to inhibit conserved signaling pathways in their Drosophila hosts. We have found that distinct parasitoid species target specific signaling pathways in their hosts, including species that specifically inhibit the JAK-STAT, NFκB and JNK signal transduction pathways. These pathways play vital roles in human health and this research will provide important insight into their regulation. 2) Characterizing the ability of predicted dominant negative proteins to regulate host signaling. Our bioinformatic analyses have identified several putative dominant negative proteins within parasitoid venom. We predict that these proteins will deregulate diverse signaling activities including immune receptor signaling and cytoskeletal rearrangements. From these experiments we will gain a better understanding of the roles played by the targeted proteins in a range of signaling events. 3) Investigating the basis for the tissue specificity of parasitoid venom activity. We have found that the ability of parasitoids to regulate signaling is highly tissue specific within the host. These experiments will explore the basis of this observation and provide insight into the mechanisms that underlie tissue specific signal regulation. The knowledge gained from this research will help to elucidate general principles underlying the regulation of signaling, and will provide specific information about multiple pathways and signaling mechanisms linked to human health. In addition, these findings could be applied to the development of new therapeutics that could be utilized for a variety of human diseases that share common molecular mechanisms.

细胞内和细胞间信号事件的精确调节对于生物学的功能至关重要 系统并在人类健康中起着至关重要的作用。放松调节的信号传导可以通过 改变信号活性的时间或强度，并可能有助于多种疾病的发病机理。 信号调节是通过多种固有机制来完成的，但也可以操纵信号传导 通过外在因素，包括来自其他生物或环境的因素。有生物的信号 在感染期间经常观察到调节，其中寄生虫可以利用病毒因素以改变 主机信号事件。在我的实验室中，我们使用果蝇 - 寄生虫黄蜂宿主 - 寄生虫系统作为模型 研究寄生虫用来操纵宿主信号的机制。这些寄生虫含有病毒 毒液中的蛋白质以及我实验室的工作表明寄生虫毒素可以修饰 配置的信号机制，包括信号传输途径和第二使者系统 他们的主人。了解这些毒液蛋白活性的机械基础将提供强大的工具 研究信号事件的调节，并将使我们能够对构成信号的新洞察力进行新的见解 果蝇的机制，这是人类健康的重要模型。我们研究的目的是利用 该系统揭示了信号调节基础的新机制并实现这些目标，研究 我的实验室将重点关注：1）识别寄生虫黄蜂使用以抑制构成的分子机制 果蝇宿主中的信号通路。我们发现不同的寄生虫规格目标特定 宿主中的信号通路，包括专门抑制JAK-STAT，NFκB和JNK的物种 信号传输途径。这些途径在人类健康中起着至关重要的作用，这项研究将提供 对他们的监管的重要洞察力。 2）表征预测的主要负蛋白的能力 调节主机信号。我们的生物信息学分析已经确定了几种推定的显性负蛋白 在寄生的毒液中。我们预测这些蛋白质将放松管制潜水信号活动，包括 免疫接收器信号传导和细胞骨架重排。从这些实验中，我们将获得更好的 了解目标蛋白在一系列信号事件中扮演的角色。 3）调查 寄生虫活性的组织特异性的基础。我们发现寄生虫的能力 调节信号传导在宿主中是高度组织特异性的。这些实验将探讨这一点的基础 观察并提供有关组织特定信号调节基础的机制。 从这项研究中获得的知识将有助于阐明监管的基础的一般原则 信令，并将提供有关多种途径和信号机制的特定信息 人类健康。此外，这些发现可以应用于新疗法的开发 用于共享共同分子机制的多种人类疾病。