Regulation of Host Signaling by Parasitoid Venom Proteins

对细胞内和细胞间信号事件的精确调控对于生物的功能至关重要 并对人类健康起着至关重要的作用。放松管制的信号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。 信号调节是由各种内在机制完成的，但信号也可以被操纵 外在因素，包括源自其他生物或环境的因素。生物间信号 在感染过程中经常观察到调节，在这种情况下，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-寄主-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。这些寄生蜂含有毒力 在它们的毒液中的蛋白质，我的实验室的工作已经证明了寄生蜂的毒液蛋白质可以修饰 保守的信号机制，包括信号转导通路和第二信使系统 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，将使我们对保守的信号有新的认识 人类健康的重要模型--果蝇的机制。我们研究的目的是利用 为了发现潜在的信号调节的新机制并实现这些目标，在 我的实验室将专注于：1)鉴定寄生蜂用来抑制保守的分子机制 果蝇寄主体内的信号通路。我们已经发现，不同的寄生蜂物种针对特定的 寄主中的信号通路，包括特异性抑制JAK-STAT、NFκB和JNK的物种 信号转导通路。这些通路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洞察。2)表征预测的显性负蛋白的能力 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蛋白 在寄生蜂的毒液中。我们预测，这些蛋白质将解除对不同信号活动的调控，包括 免疫受体信号和细胞骨架重排。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扮演的角色。3)调查 为寄生蜂毒液活性的组织特异性奠定基础。我们已经发现，寄生蜂的能力 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点的基础 观察并洞察组织特异性信号调节的机制。这个 从这项研究中获得的知识将有助于阐明监管的一般原则 信令，并将提供有关链接到的多个路径和信令机制的特定信息 人类健康。此外，这些发现可以应用于新疗法的开发，这种疗法可以 可用于治疗多种人类疾病，这些疾病具有共同的分子机制。

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.