Exploring the Venom Repertoire of Parasitoids

描述(申请人提供)：寄生蜂是大量自由生活的昆虫，它们将毒液注射到其他昆虫中，然后在其他昆虫上产卵。寄生蜂在它们所利用的宿主(苍蝇、甲虫、蝴蝶等)、它们寄生的生活期(卵、幼虫、蛹)以及它们的卵是在宿主内还是在宿主外产卵和发育方面有所不同。由于这种多样性，寄生蜂毒液进化出不同的机制来控制寄主免疫、生理和行为，以促进寄生蜂幼虫的发育。在它们的作用中，毒液可以引起暂时或永久性的瘫痪，选择性的细胞凋亡，以及宿主脂质生理、免疫和行为的改变。然而，关于单个寄生蜂毒液蛋白的多样性或功能，人们几乎一无所知。有超过15万种寄生蜂。仅模式寄生的丽纹夜蛾就有至少79个不同的毒液基因，其中24个与任何已知蛋白质没有序列相似性，也不包含已知的保守结构域。考虑到它们令人难以置信的数量和多样性，寄生虫毒液是一种巨大的、尚未开发的药物发现潜在资源。挑战是有效地评估这一具有医疗和研究应用的分子的巨大潜在药典。小分子生物活性多肽作为治疗药物特别有前景，因此检测它们在寄生蜂毒液中的作用是一个重要的目标。我们预测，新的毒液蛋白的进化保守性可用于鉴定具有与药物和研究相关的生物活性的短肽。如果正确，这种方法可能会在巨大的寄生蜂毒液蛋白池中迅速加速新药发现。在这里，我们建议通过转录组、蛋白质组和生理图谱的方法来研究(A)单个的Nasonia毒液蛋白在整个动物(肉蝇)和人类细胞系中的作用，(B)评估寄生蜂毒液进化的多样性并识别保守的短肽，以及(C)使用我们的整个动物和人类细胞系分析来检验进化保守性可以用于预测短生物活性多肽的假设。该项目结合了遗传学、蛋白质组学、生理学和进化论的方法，在巨大的寄生蜂毒液蛋白池中探索功能、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.