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

描述（由申请人提供）：动物毒液是一种复杂的毒素混合物，含有数百种成分，包括具有精细目标特异性的神经毒素。他们对潜在的毒素发现感兴趣，这些毒素具有新的目标特异性，可用于药物或神经生理学研究。它们也引起了人们的兴趣，因为某些物种的毒液会对人类造成伤害。蜘蛛，由于其毒液的复杂性（单个蜘蛛中含有200- 1000种毒素）和数量众多的物种（约42000种已被描述！），被预测包含所有有毒谱系中最大的毒素多样性池，但它们的毒液仍然很少被探索。此外，对蜘蛛毒液毒素的进化动力学分析很少。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血清疗法发展的指南。这个项目的目标是比较进化分析的全套毒液成分（“毒液”）之间的种类的蜘蛛。吸血蜱包括臭名昭著的褐隐士和他们的亲戚，他们的叮咬能够引起皮肤萎缩性病变和全身影响。昆虫共有约125种，它们之间的差异代表了它们共同祖先以来1亿年的进化。它们也属于蜘蛛亚目（单倍体），其中对毒液知之甚少。在Specific Aim 1中，我们将使用转录组学和蛋白质组学相结合的方法来表征吸血蝇科所有主要谱系和两个外群的毒液表达蛋白和肽的补体。在具体目标2中，我们将使用计算生物学方法来分析毒素个体谱系的进化动力学（复制模式、选择证据、结构基序），并对它们进行比较，以推断该谱系中毒素的保护程度和变异程度。这些数据将提供一个全面的观点，蛋白质和肽成分的棕色隐士及其亲属的毒液，促进评估可能的贡献目前尚未表征的毒素对人体的毒性反应。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的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动的毒液毒素的平台。初步数据表明，我们可能会发现与目前已知的毒素有很大不同的毒素。

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