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Comparative venomes of recluse spiders and kind: treatments and toxin discovery

隐士蜘蛛及其种类的毒液比较：治疗方法和毒素发现

基本信息

批准号：
8879895
负责人：
Greta Jeanne Binford
金额：
$ 26.6万
依托单位：
LEWIS AND CLARK COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8879895
关键词：
Amino Acids Animals Antivenins Basic Science Bite Chemicals Complementary DNA Complex Complex Mixtures Computational Biology Cytotoxin Data Databases Development Diagnostic Drug Targeting Effectiveness Evolution Family Freezing Funding Gene Expression Profile Gene Family Genealogical Tree Genome Gland Goals Health Homologous Gene Human Individual Insecticides Lesion Life Medical Methods Modeling Molecular Evolution Morphologic artifacts Neurotoxins Pain Pattern Peptides Pharmaceutical Preparations Phylogenetic Analysis Physiological Positioning Attribute Process Protein Family Proteins Proteome Proteomics RNA Recruitment Activity Relative (related person)Relative Risks Research Set protein Specificity Spider Venoms Spiders Staging Taxon Tissues Toxin Transcript Trees United States National Institutes of Health Variant Venoms Work antimicrobial cDNA Library chemical function comparative drug discovery insight interest neurophysiology next generation sequencing novel response species difference sphingomyelin phosphodiesterase D therapy development

项目摘要

DESCRIPTION (provided by applicant): Animal venoms are complex mixtures of toxic components, including neurotoxins and cytotoxins with exquisite target specificity. Toxins with unique activities are of interest for drugs and neurophysiological research. Spiders, because of their venom complexity (200-1000 toxins in a single spider) and diversity (>44,500 described species!), likely contain the largest pool of toxin diversity of any venomous taxon, yet most major spider lineages are unexplored. Moreover, the field is in early stages of understanding evolutionary dynamics generating venom toxin diversity. With new availability of complete venom transcriptomes and the first spider genomes it is now possible to understand venom diversity and evolution at a new level of sophistication. 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 to understand the phylogenetic scale at which there are significant differences in venom composition among spider taxa, and to infer mechanisms of evolution that contribute to these differences. This project continues comparative analyses of venomes in sicariid spiders and Haplogyne relatives. Sicariids include the notorious brown recluse whose bites cause dermonecrotic lesions and systemic effects in humans. There are ~130 described species and differences among them represent over ~120 million years of evolution since their most recent common ancestor. Evidence indicates the toxin responsible for dermonecrosis was recruited for venom function before the most recent common ancestor of the lineage. Sicariids are in the Haplogyne suborder within which, before this work, very little was known about venoms. Funded by NIH R15-GM-097696-01, cDNA transcriptomes for five sicariid taxa, three haplogynes and one outgroup were created and screened to produce nearly 5,000 venom gland transcripts. Combined with venom proteomics the minimal phylogenetic breadth of over 15 venom-expressed toxins was identified. However, these data are not comprehensive and missing toxins could reflect real absence, or artifacts of methods. There are three specific aims for this renewal: (1) to more thoroughly assess the phylogenetic distribution of venom toxin lineages across sicariids and haplogynes by adding next generation sequencing data; (2) to identify and analyze the gene families from which venom toxins were recruited by identifying non- venom expressed homologs in body transcriptomes and in the genome of Loxosceles reclusa; (3) to analyze evolutionary dynamics (duplications and selection) of individual lineages of toxins and compare them to identify parallel patterns in the evolution of toxins in the same venom functional complex. The toxins discovered in this work are a platform for discovery of natural components that contain unique neurophysiological activities. Preliminary data indicate discovery of divergent and unique toxins.

描述（由申请人提供）：动物毒液是由多种毒性成分组成的复杂混合物，包括神经毒素和细胞毒素，具有高度的靶向特异性。具有独特活性的毒素在药物和神经生理学研究中具有重要意义。蜘蛛，由于其毒液的复杂性（单个蜘蛛中有200-1000种毒素）和多样性（超过44，500种描述的物种！），可能含有最大的毒素库任何有毒分类群的多样性，但大多数主要的蜘蛛谱系是未经探索的。此外，该领域还处于理解产生毒液毒素多样性的进化动力学的早期阶段。随着新的完整毒液转录组和第一个蜘蛛基因组的可用性，现在有可能在一个新的复杂水平上了解毒液的多样性和进化。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。该项目的目标是了解蜘蛛类群之间毒液成分存在显着差异的系统发育尺度，并推断导致这些差异的进化机制。该项目继续比较分析蜘蛛科蜘蛛和Haplogyne亲属的毒液。Sicariids包括臭名昭著的棕色隐士，其叮咬导致人类皮肤坏死和全身影响。有大约130个描述的物种，它们之间的差异代表了自最近的共同祖先以来超过1.2亿年的进化。有证据表明，负责皮肤坏死的毒素在该谱系最近的共同祖先之前被招募用于毒液功能。Sicariids属于Haplogyne亚目，在这项工作之前，对毒液知之甚少。在NIH R15-GM-097696-01的资助下，创建并筛选了5个蜱类分类群、3个单雌蜱和1个外群的cDNA转录组，产生了近5,000个毒腺转录本。结合毒液蛋白质组学，确定了超过15种毒液表达毒素的最小系统发育宽度。然而，这些数据并不全面，缺失的毒素可能反映了真实的缺失或方法的人为因素。该更新有三个具体目的：（1）通过添加下一代测序数据来更彻底地评估毒液毒素谱系在蜱类和单雌类中的系统发育分布;（2）通过鉴定在体转录组中和在Loxosceles reclusa的基因组中的非毒液表达同源物来鉴定和分析毒液毒素从其募集的基因家族;（3）分析毒素的各个谱系的进化动力学（复制和选择），并将它们进行比较，以确定相同毒液功能复合物中毒素进化的平行模式。这项工作中发现的毒素是发现含有独特神经生理活性的天然成分的平台。初步数据表明发现了不同的独特毒素。