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传导事件的精确调节对于生物功能至关重要 系统并在人类健康中发挥着重要作用。信号传导失调可以通过以下方式扰乱细胞功能： 改变信号活动的时间或强度，可能导致多种疾病的发病机制。 信号调节是通过多种内在机制完成的，但信号传导也可以被操纵 受外在因素影响，包括来自其他生物体或环境的因素。生物体间信号 在感染过程中经常观察到调节，其中寄生虫可以利用毒力因子来改变 主机信令事件。在我的实验室中，我们使用果蝇寄生蜂宿主寄生虫系统作为模型 研究寄生虫操纵宿主信号传导的机制。这些寄生蜂含有毒力 我的实验室的工作表明，寄生蜂毒液中的蛋白质可以修饰 保守的信号传导机制，包括信号转导途径和第二信使系统 他们的主人。了解这些毒液蛋白活性的机制基础将提供一个强大的工具 研究信号事件的调节，并使我们能够对保守信号获得新的见解 果蝇的机制，人类健康的重要模型。我们研究的目的是利用 该系统旨在揭示信号调节背后的新机制并实现这些目标，研究 我的实验室将重点关注：1）确定寄生蜂用来抑制保守性的分子机制 果蝇宿主中的信号通路。我们发现不同的寄生蜂物种针对特定的目标 宿主体内的信号通路，包括特异性抑制 JAK-STAT、NFκB 和 JNK 的物种 信号转导途径。这些途径在人类健康中发挥着至关重要的作用，这项研究将提供 对其监管的重要见解。 2) 表征预测的显性失活蛋白的能力 调节宿主信号传导。我们的生物信息分析已经确定了几种推定的显性失活蛋白 寄生蜂毒液内。我们预测这些蛋白质将解除对多种信号活动的管制，包括 免疫受体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结果 了解目标蛋白在一系列信号事件中所起的作用。 3）调查 寄生蜂毒液活性的组织特异性的基础。我们发现寄生蜂有能力 调节信号在宿主内具有高度的组织特异性。这些实验将探索这一基础 观察并深入了解组织特异性信号调节的机制。这 从这项研究中获得的知识将有助于阐明监管的一般原则 信号传导，并将提供有关多种途径和信号传导机制的具体信息 人类健康。此外，这些发现可以应用于新疗法的开发 可用于治疗具有共同分子机制的多种人类疾病。