Chemical Biodiversity: Investigating the Phylogeny and Functional Toxins of Venom

描述(申请人提供)：细胞通讯和功能依赖于离子通道和受体介导的电化学信号。了解这些通道和受体是如何发挥作用的，以及如何操纵它们产生的电信号，将使研究人员对大量的细胞生理学有重要的见解，包括细胞信号、神经元功能和关于大分子机器的一般信息。迫切需要确定新的配体，以表征参与细胞信号传递的离子通道和受体。在研究中枢神经系统细胞通讯的重要工具中，有毒海洋蜗牛的毒素就是其中之一。锥螺科(Conidae；Linneeus，1758年)、螺旋螺类或杂交类(Terebridae；Morch，1852年)和斑鳖(Turridae；图1：有毒海洋蜗牛的多样性)。A.锥螺科(锥螺)。B.Terebridae(螺旋螺)。Swainson 1840)属于弓形虫(“有毒”)C.Turridae(斑鳖)。有毒软体动物的超级家族(Fleming，1822)，产生独特的多肽毒素以捕食其他海洋动物(图1)。这种超多样化的腹足类群所使用的各种毒素来征服鱼类、蠕虫和其他海洋生物，为生态如何影响发育和进化变化提供了一个理想的系统发育模型。此外，在弓形虫毒液中发现的毒素的药理和生物多样性为研究离子通道和受体提供了一个充满活力且基本上未被开发的储存库。本申请中概述的研究计划是基于一种跨学科的方法，将快速增长的化学生物学领域与分类学和系统发育学相结合。拟议的研究目标是重建促进有毒海洋蜗牛和其他生物多样性中发现的毒素多样性的进化生物学，并使用系统发育假说来了解它们的毒素的生化和遗传特征。这项拟议的研究将通过从有毒的海洋蜗牛中识别具有潜在治疗相关应用的新配体，推动离子通道和神经元受体的研究。锥螺毒素在药理上的成功使它们被生物化学家和神经学家广泛使用，但对陆栖动物和其他弓形虫的毒素知之甚少，这些家族的系统发育在很大程度上是有疑问的。在自然界的一个科学转折中，来自弓舌类软体动物的毒液开始闪耀着贝壳的外表之美。这份提案概述了一个合作项目，旨在帮助PI开发一个具有竞争力和活力的研究计划。在开创了Terebridae的第一个分子系统学[1]之后，拟议研究的目标是：i)记录和了解Toxoglossa(Conoidae)超家族Terebridae的生物多样性和系统发育。二)确定新的土豆和土豆毒素及其编码基因的特征，以确定可用于研究中枢神经系统细胞通讯和潜在疗法的新化合物。Iii)与其他研究人员合作，将生物多样性+化学生物学战略扩展到其他具有生物活性分子的动物群体。一项全面的指导计划将满足发展需求，因为它们涉及到PIS的科学成就、学生和博士后研究员的培训以及独立的职业发展。 公共卫生相关性：锥螺毒素在药理学上的成功使其被生物化学家和神经学家广泛使用，但对陆栖动物和其他弓形虫的毒素知之甚少，这些家族的系统发育在很大程度上是值得怀疑的。在自然界的一个科学转折中，来自弓舌类软体动物的毒液开始闪耀着贝壳的外表之美。这份提案概述了一个合作项目，旨在帮助PI开发一个具有竞争力和活力的研究计划。在开创了Terebridae的第一个分子系统学[1]之后，拟议研究的目标是：i)记录和了解Toxoglossa(Conoidae)超家族Terebridae的生物多样性和系统发育。二)确定新的土豆和土豆毒素及其编码基因的特征，以确定可用于研究中枢神经系统细胞通讯和潜在疗法的新化合物。Iii)与其他研究人员合作，将生物多样性+化学生物学战略扩展到其他具有生物活性分子的动物群体。一项全面的指导计划将满足发展需求，因为它们涉及到PIS的科学成就、学生和博士后研究员的培训以及独立的职业发展。

DESCRIPTION (provided by applicant): Cellular communication and function depend on electrochemical signals mediated by ion channels and receptors. Knowledge of how these channels and receptors function and how to manipulate the electrical signals they produce would give researchers significant insights into a plethora of cell physiologies, including cell signaling, neuronal functions, and general information about macromolecular machines. There is pressing need to identify novel ligands specific for characterizing ion channels and receptors involved in cell signaling. Among the important tools identified for investigating cellular communication in the central nervous system are the toxins from venomous marine snails. Cone snails (Conidae; Linnaeus, 1758), auger snails or terebrids (Terebridae; Morch, 1852), and turrids (Turridae; Figure 1: Diversity of venomous marine snails. A. Conidae (cone snails). B. Terebridae (auger snails). Swainson 1840) belong to the Toxoglossate ("poison-tonuged") C. Turridae (turrids). super family (Fleming, 1822) of venomous mollusks that produce unique peptide toxins to predate on other marine animals (Figure 1). The varied arsenal of toxins employed by this hyper diverse group of gastropods to subdue fish, worms, and other marine organisms, provides an ideal phylogenetic model for how ecology impacts development and evolutionary change. Additionally, the pharmacological and biological diversity of the toxins found in Toxoglossate venoms present a vibrant and largely unexplored repository for investigating ion channels and receptors. The research program outlined in this application is based on an interdisciplinary approach combining the rapidly growing field of chemical biology with taxonomy and phylogenetics. The proposed research goals are to reconstruct the evolutionary biology that motivates the diversity of toxins found in venomous marine snails and other biodiverse organisms, and use the phylogenetic hypotheses to inform the biochemical and genetic characterization of their toxins. The proposed research will advance the investigation of ion channels and neuronal receptors by identifying novel ligands from venomous marine snails with potentially therapeutically relevant applications. The pharmacological success of toxins from cone snails has led to their extensive use by biochemists and neurologists, but very little is known about toxins from terebrids and other Toxoglossa, and the phylogeny of these families is largely in doubt. In a scientific twist of nature, the venoms from Toxoglossate mollusks are beginning to out shine the exterior beauty of the shells. This proposal outlines a collaborative project designed to help the PI develop a competitive and vigorous research program. Having initiated the first molecular phylogeny of the Terebridae [1], the goals of the proposed research are to: I) Document and understand the biodiversity and phylogeny of the Terebridae in the Toxoglossa (Conoidea) super family. II) Characterize novel terebrid and turrid toxins, and the genes that encode them, in order to identify novel compounds useful for investigating cellular communication in the central nervous system and potential therapeutics. III) Collaborate with other investigators to extend the biodiversity + chemical biology strategy to other animal groups that have bioactive molecules. A thorough mentoring plan will address development needs as they refer to the PIs scientific achievement, training of students and postdoctoral fellows, and independent career advancement. PUBLIC HEALTH RELEVANCE: The pharmacological success of toxins from cone snails has led to their extensive use by biochemists and neurologists, but very little is known about toxins from terebrids and other Toxoglossa, and the phylogeny of these families is largely in doubt. In a scientific twist of nature, the venoms from Toxoglossate mollusks are beginning to out shine the exterior beauty of the shells. This proposal outlines a collaborative project designed to help the PI develop a competitive and vigorous research program. Having initiated the first molecular phylogeny of the Terebridae [1], the goals of the proposed research are to: I) Document and understand the biodiversity and phylogeny of the Terebridae in the Toxoglossa (Conoidea) super family. II) Characterize novel terebrid and turrid toxins, and the genes that encode them, in order to identify novel compounds useful for investigating cellular communication in the central nervous system and potential therapeutics. III) Collaborate with other investigators to extend the biodiversity + chemical biology strategy to other animal groups that have bioactive molecules. A thorough mentoring plan will address development needs as they refer to the PIs scientific achievement, training of students and postdoctoral fellows, and independent career advancement.