Genomics-based Venom Studies Using the Cone Snail C. Bullatus

描述(申请人提供)：使用锥形蜗牛进行基于基因组学的毒液研究。海洋蜗牛Conus Bullatus是一种捕食性鱼类，必须迅速固定猎物。这是通过向猎物注射致命的螺杆菌多肽毒液鸡尾酒来实现的，这些毒液是富含半胱氨酸的小肽，每一种都与不同的配体或电压门控离子通道有很高的亲和力。在过去的十年里，锥形毒液被证明是研究脊椎动物神经传递不可或缺的试剂，FDA已经批准了一种用于治疗慢性疼痛的试剂。有充分的理由相信，总体而言，锥形蜗牛仍然藏有大量具有药理价值的未定性毒液(10万英镑)。刀豆肽还经历了许多不寻常的翻译后修饰，这些修饰是由本身具有药理意义的酶进行的。这种毒液成熟的过程没有得到很好的描述。不幸的是，由于缺乏重要的基因组资源，今天的锥体毒液研究受到阻碍。因此，这项申请的目的是(1)获得资金用于Conus转录组和基因组测序和分析，以确定新的毒液及其翻译后修饰因子，以及(2)这些新毒液及其翻译后修饰所涉及的酶的功能特性。。 与公共卫生相关：该项目将使用大量DNA和RNA测序来识别和表征锥形蜗牛的新毒液基因。这一点很重要，因为这些毒液对脊椎动物的神经生物学研究和控制慢性疼痛的药物都很有用。因此，发现和鉴定更多的锥体毒液将促进基础研究和人类健康。

DESCRIPTION (provided by applicant): Genomics-based venom studies using the cone snail C. bullatus. The marine snail, Conus bullatus is a fish predator and must quickly immobilize its prey. This is accomplished by injecting prey with a lethal cocktail of conopeptide venoms, small cysteine-rich peptides, each with a high affinity to a different ligand or voltage- gated ion channel. Over the last decade, cone venoms have proven indispensable reagents for the study of vertebrate neurotransmission, and the FDA has approved one for the treatment of chronic pain. There is good reason to believe that collectively the cone snails still harbor a large repertoire of uncharacterized venoms (<100,000) of pharmacological interest. Conopeptides also undergo many unusual posttranslational modifications, carried out by enzymes that are themselves of pharmacological interest. This process of venom maturation is poorly characterized. Unfortunately, cone venom research today is hindered by a lack of significant genomic resources. Hence, the purpose this application is (1) to obtain funds for Conus transcriptome and genome sequencing and analyses to identify new venoms and their posttranslational modifiers, and (2) for functional characterizations of these new venoms and the enzymes involved in their posttranslational modifications. . PUBLIC HEALTH RELEVANCE: This project will use high-volume DNA and RNA sequencing to identify and characterize new venom genes in cone snails. This is important because these venoms are useful for vertebrate neurobiology research and as drugs for control of chronic pain. Discovering and characterizing more cone venoms will thus further both basic research and human health.