Chemical Biodiversity: Investigating the Phylogeny and Functional Toxins of Venom

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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.