Comparative "venomes" of recluse spiders and their kin: treatments and toxin disc

隐士蜘蛛及其亲属的“毒液”比较：治疗方法和毒素盘

• 批准号: 8099398
• 负责人: Greta Jeanne Binford
• 金额: $ 26.08万
• 依托单位: LEWIS AND CLARK COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099398
• 关键词: Animals; Antivenins; Basic Science; Bite; Chemicals; Complement; Complex Mixtures; Computational Biology; Country; Data; Development; Diagnostic; Drug usage; Effectiveness; Evolution; Family; Gene Expression Profile; Gene Family; Genealogical Tree; Gland; Goals; Human; Individual; Lesion; Life; Medical; Modeling; Neurotoxins; Pattern; Peptides; Phylogenetic Analysis; Physiological; Positioning Attribute; Process; Protein Family; Proteins; Proteome; Proteomics; Relative (related person); Relative Risks; Research; Specificity; Specimen; Spider Venoms; Spiders; Tissues; Toxin; Trees; Variant; Venoms; Work; chemical function; comparative; drug discovery; effective therapy; insight; interest; neurophysiology; novel; response; sphingomyelin phosphodiesterase D; transcriptomics

DESCRIPTION (provided by applicant): Animal venoms are complex mixtures of toxins with single species containing hundreds of components including neurotoxins with exquisite target specificity. They are of interest for potential discovery of toxins with novel target specificities that could be used for drugs or neurophysiological research. They also are of interest because of the damage to humans caused by venoms of some species. Spiders, because of the complexity of their venoms (200- 1000 toxins in a single spider) and large number of species (~42,000 described!), are predicted to contain the largest pools of toxin diversity of any venomous lineages, yet their venoms remain little explored. Moreover, very few analyses have been done on the evolutionary dynamics of spider venom toxins. Insight into evolutionary mechanisms influencing venoms can serve as a guide for toxin discovery and development of antivenom therapies. The goal of this project is a comparative evolutionary analysis of the full set of venom components ("venomes") among species of sicariid spiders. Sicariids include the notorious brown recluse and their relatives whose bites are capable of causing dermonecrotic lesions and systemic effects in humans. There are ~125 species of sicariids and differences among them represent 100 million years of evolution since their common ancestor. They are also in a spider suborder (Haplogynes) within which very little is known about venoms. In Specific Aim 1 we will use combined transcriptomic and proteomic approaches to characterize the complement of venom-expressed proteins and peptides in representatives of all major lineages of Sicariidae and two outgroups. In Specific Aim 2 we will use computational biology approaches to analyze evolutionary dynamics (duplication patterns, evidence of selection, structural motifs) of individual lineages of toxins and compare them to infer the degree of conservation and variation among toxins in this lineage. These data will provide a comprehensive view of protein and peptide components in venoms of brown recluse and their relatives, facilitating assessment of the possible contribution of currently uncharacterized toxins to the human response to envenomation. Patterns of similarity and differences among species will help with understanding relative risks associated with bites across species, and with developing diagnostics and treatments that are effective for bites from species across the entire genus. The data will also be a platform for discovery of venom toxins with unique neurophysiological activities. Preliminary data indicate we are likely to discover toxins that are significantly divergent from those that are currently known. PUBLIC HEALTH RELEVANCE: The data collected in this work will provide a comprehensive view of protein and peptide components in venoms of brown recluse and their relatives, facilitating assessment of the possible contribution of currently uncharacterized toxins to the human response to envenomation. Patterns of similarity and differences among species will help with understanding relative risks associated with bites across species, and with developing diagnostics and treatments that are effective for bites from species across the entire family. The data will also be a platform for discovery of venom toxins with unique neurophysiological activities

描述（由申请人提供）：动物毒液是毒素的复杂混合物，单一物种含有数百种组分，包括具有精确靶向特异性的神经毒素。它们对于潜在发现具有可用于药物或神经生理学研究的新型靶特异性的毒素是有意义的。它们也是人们感兴趣的，因为某些物种的毒液会对人类造成伤害。蜘蛛，因为它们的毒液的复杂性（200- 1000毒素在一个单一的蜘蛛）和大量的物种（~42,000描述！），据预测，在所有有毒的谱系中，它们的毒素多样性最大，但它们的毒液仍然很少被探索。此外，很少有人对蜘蛛毒液毒素的进化动力学进行分析。深入了解影响毒液的进化机制可以作为毒素发现和抗蛇毒疗法开发的指导。这个项目的目标是比较分析所有种类的蜘蛛毒液成分（“毒液组”）的进化。Sicariids包括臭名昭著的棕色隐士及其亲属，其叮咬能够导致人类皮肤坏死性病变和全身效应。有约125种的sicariids和它们之间的差异代表了1亿年的进化以来，他们的共同祖先。它们也属于蜘蛛亚目（单雌蛛），其中对毒液的了解很少。在具体目标1中，我们将使用组合的转录组学和蛋白质组学方法来表征所有主要谱系的Sicariidae和两个外类群的代表中的毒液表达的蛋白质和肽的补充。在具体目标2中，我们将使用计算生物学方法来分析毒素的各个谱系的进化动力学（复制模式，选择的证据，结构基序），并将它们进行比较，以推断该谱系中毒素之间的保守性和变异程度。这些数据将提供一个全面的看法，蛋白质和肽成分的毒液的棕色隐士和他们的亲属，促进评估可能的贡献，目前未知的毒素对人类的反应envenomation。物种之间的相似性和差异模式将有助于了解与跨物种叮咬相关的相对风险，并有助于开发对整个属物种叮咬有效的诊断和治疗方法。这些数据也将成为发现具有独特神经生理活性的毒液毒素的平台。初步数据表明，我们可能会发现与目前已知的毒素截然不同的毒素。 公共卫生相关性：在这项工作中收集的数据将提供一个全面的看法，蛋白质和肽成分的毒液的棕色隐士和他们的亲属，促进评估可能的贡献，目前未知的毒素对人类的反应envenomation。物种之间的相似性和差异模式将有助于了解与跨物种叮咬相关的相对风险，并有助于开发对整个家族物种叮咬有效的诊断和治疗方法。这些数据也将成为发现具有独特神经生理活性的毒液毒素的平台