Exploring the Venom Repertoire of Parasitoids

描述（由申请人提供）：拟寄生蜂是一种大量的自由生活的昆虫，它们将毒液注入其他昆虫体内，然后在其他昆虫身上产卵。寄生蜂利用的寄主（苍蝇、甲虫、蝴蝶等）、寄生的生命阶段（卵、幼虫、蛹）以及它们的卵是在寄主内还是在寄主外产卵和发育等方面各不相同。由于这种多样性，寄生性毒液已经进化出不同的机制来操纵宿主的免疫、生理和行为，以促进寄生性幼虫的发育。在它们的作用中，毒液可以诱导暂时或永久性瘫痪、选择性凋亡和宿主脂质生理、免疫和行为的改变。然而，对单个类寄生虫毒液蛋白的多样性或功能几乎一无所知。有超过15万种拟寄生物。单是模型拟寄生虫玻喙纳索尼亚至少有79种不同的毒液基因，其中24种与任何已知的蛋白质序列没有相似性，并且不包含已知的保守结构域。鉴于其惊人的数量和多样性，类寄生虫毒液代表着一种巨大的、尚未开发的药物开发潜力资源。我们面临的挑战是如何有效地评估这一具有巨大潜力的具有医学和研究应用的分子药典。小生物活性肽作为治疗药物尤其有前景，因此它们在类寄生虫毒液中的检测是一个重要的目标。我们预测，新的毒液蛋白的进化守恒可以用来识别与医学和研究相关的生物活性短肽。如果正确的话，这种方法可以迅速加速在巨大的类寄生虫毒液蛋白池中发现新的药物。在这里，我们建议通过转录组、蛋白质组和生理分析来研究(a)单个纳索蝇毒液蛋白在整个动物bullata（肉蝇）和人类细胞系中的作用，(b)评估拟寄生虫毒液进化的多样性并鉴定保守的短肽，(c)通过我们的整个动物和人类细胞系实验来验证进化保守性可以用来预测短生物活性肽的假设。该项目结合了遗传学、蛋白质组学、生理学和进化的方法来探索巨大的类寄生虫毒液蛋白池的功能、多样性和药物发现的潜力。

DESCRIPTION (provided by applicant): Parasitoid wasps are abundant free-living insects that inject venom into and then lay their eggs on other insects. Parasitoids vary in hosts they utilize (flies, beetles, butterflies, etc), the life stage they parasitize (eggs, larvae, pupae), and whether their eggs are laid and develop within or outside the host. Due to this diversity, parasitoid venoms have evolved different mechanisms for manipulating host immunity, physiology and behavior in ways that enhance development of the parasitoid young. Among their effects, venoms can induce temporary or permanent paralysis, selective apoptosis, and alterations in host lipid physiology, immunity, and behavior. Yet virtually nothing is known about the diversity or function of individual parasitoid venom proteins. There are over 150,000 species of parasitoids. The model parasitoid Nasonia vitripennis alone has at least 79 different venom genes, of which 24 have no sequence similarity to any known proteins and contain no known conserved domains. Given their incredible number and diversity, parasitoids venoms represent an immense and untapped potential resource for drug discovery. The challenge is to efficiently assess this immense potential pharmacopeia for molecules with medical and research applications. Small biologically active peptides are particularly promising as therapeutic agents, and therefore their detection in parasitoid venoms is an important goal. We predict that evolutionary conservation in novel venom proteins can be used to identify short peptides with biological activity of relevance to medicine and research. If correct, this approach could rapidly accelerate new drug discovery among the immense pool of parasitoid venom proteins. Here we propose to investigate (a) the effects of individual Nasonia venom proteins in the whole animal Sarcophaga bullata (flesh fly) and in human cell lines by transcriptome, proteome, and physiological profiling, (b) assess the diversity of evolution of parasitoid venoms and identify conserved short peptides, and (c) test the hypothesis that evolutionary conservation can be used to predict short bioactive peptides, using our whole animal and human cell line assays. The project combines genetic, proteomic, physiological and evolutionary approaches to explore function, diversity, and potential for drug discovery in the immense pool of parasitoid venom proteins.