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: 10654581
• 负责人: Nathan Terry Mortimer
• 金额: $ 22.46万
• 依托单位: OREGON 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654581
• 关键词: Bioinformatics; Biological Process; Cell physiology; Cytoskeleton; Development; Disease; Dominant-Negative Mutation; Drosophila genus; Environment; Event; Goals; Health; Human; Immunologic Receptors; Infection; Knowledge; 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; parasite invasion; 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学功能至关重要。 系统，并在人类健康中发挥重要作用。失调的信号传导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，并可能导致多种疾病的发病机制。 信号调节是由多种内在机制完成的，但信号也可以被操纵 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 在感染期间经常观察到调节，其中寄生虫可以利用毒力因子以改变 主机信号事件。在我的实验室里，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的机制。这些拟寄生蜂含有毒力 我实验室的工作已经证明，寄生虫毒液蛋白可以改变它们毒液中的蛋白质， 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有力的工具 研究信号事件的调节，并将使我们能够对保守的信号转导获得新的见解 果蝇是人类健康的重要模型。我们研究的目的是 该系统揭示了信号调节的新机制，并实现这些目标，研究 我的实验室将集中于：1）确定寄生蜂抑制保守的 果蝇宿主中的信号通路。我们已经发现，不同的寄生虫物种的目标具体 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起着至关重要的作用，这项研究将提供 对他们的监管有重要的见解。2)表征预测的显性负性蛋白质的能力， 调节宿主信号。我们的生物信息学分析已经确定了几个假定的显性负性蛋白质 寄生蜂毒液中的一种我们预测，这些蛋白质将解除多种信号活动，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 了解靶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。我们已经发现，拟寄生蜂的能力， 调节信号传导在宿主内是高度组织特异性的。这些实验将探索这一点的基础 观察并提供深入了解组织特异性信号调节的机制。的 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，并将提供有关多种途径和信号机制的具体信息， 人体健康此外，这些发现可以应用于开发新的治疗方法， 用于具有共同分子机制的多种人类疾病。

项目成果

The S1A protease family members CG10764 and CG4793 regulate cellular immunity in Drosophila.

• DOI: 10.17912/micropub.biology.000370
• 发表时间: 2021-02-22
• 期刊: microPublication biology
• 作者: Kr P;Lee J;Mortimer NT
• 通讯作者: Mortimer NT

Meta-Analysis of Immune Induced Gene Expression Changes in Diverse Drosophila melanogaster Innate Immune Responses.

• DOI: 10.3390/insects13050490
• 发表时间: 2022-05-23
• 期刊: INSECTS
• 影响因子: 3
• 作者: Waring, Ashley L.;Hill, Joshua;Allen, Brooke M.;Bretz, Nicholas M.;Le, Nguyen;Kr, Pooja;Fuss, Dakota;Mortimer, Nathan T.
• 通讯作者: Mortimer, Nathan T.