Exploring the Venom Repertoire of Parasitoids

探索寄生蜂的毒液

• 批准号: 8307280
• 负责人: JOHN Haynes WERREN
• 金额: $ 30.9万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307280
• 关键词: Affect; Animals; Apoptosis; Basic Science; Behavior; Biological; Biological Assay; Biological Process; Biological Testing; Butterflies; Cell Culture Techniques; Cells; Data; Detection; Development; Drug Compounding; Evolution; Family; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genomics; Gland; Goals; Human; Human Cell Line; Immunity; Individual; Insecta; Investigation; Larva; Life; Lipids; Medical; Medical Research; Medicine; Methods; Modeling; Order Coleoptera; Paralysed; Pathway interactions; Peptides; Pharmacopoeias; Physiological; Physiology; Process; Production; Prostate; Protein Biochemistry; Proteins; Proteome; Proteomics; Pupa; RNA Interference; Research; Resources; Staging; Stretching; Taxon; Testing; Therapeutic Agents; Time; Venoms; Wasp Venoms; Wasps; Work; base; cell type; cellular targeting; drug discovery; egg; flesh fly; fly; in vivo; multidisciplinary; neuroblast; novel; preference; protein expression; protein function; protein metabolite

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.

描述（由申请人提供）：寄生蜂是大量自由生活的昆虫，它们向其他昆虫注射毒液，然后在其上产卵。拟寄生物因其利用的宿主（苍蝇、甲虫、蝴蝶等）、寄生的生命阶段（卵、幼虫、蛹）以及它们的卵是在宿主体内还是体外产下和发育而有所不同。由于这种多样性，寄生蜂毒液进化出了不同的机制来操纵宿主的免疫、生理和行为，从而促进寄生蜂幼体的发育。其中，毒液可引起暂时或永久性麻痹、选择性细胞凋亡以及宿主脂质生理、免疫和行为的改变。然而，实际上对单个寄生蜂毒液蛋白的多样性或功能一无所知。寄生蜂有超过 150,000 种。仅模型寄生蜂 Nasonia vitripennis 就具有至少 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，并且不包含已知的保守结构域。鉴于其令人难以置信的数量和多样性，寄生蜂毒液代表了药物发现的巨大且尚未开发的潜在资源。面临的挑战是如何有效评估这一具有医学和研究应用潜力的分子药典。小的生物活性肽作为治疗剂特别有前途，因此它们在寄生蜂毒液中的检测是一个重要的目标。我们预测，新型毒液蛋白的进化保守性可用于识别具有与医学和研究相关的生物活性的短肽。如果正确的话，这种方法可以迅速加速在巨大的寄生蜂毒液蛋白库中发现新药。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Nasonia毒液蛋白在整个动物Sarcophaga bullata（肉蝇）和人类细胞系中的影响，（b）评估寄生蜂毒液进化的多样性并鉴定保守的短肽，以及（c）使用我们的整体测试进化保守性可用于预测短生物活性肽的假设 动物和人类细胞系测定。该项目结合了遗传、蛋白质组学、生理学和进化方法，探索寄生蜂毒液蛋白的功能、多样性和药物发现潜力。