Conus ventricosus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA678883 | ENA |
REPOSITORIES: ENA
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Project description:?6-containing (?6*) nicotinic acetylcholine receptors (nAChRs) are expressed throughout the periphery and the central nervous system and constitute putative therapeutic targets in pain, addiction and movement disorders. The ?6?2* nAChRs are relatively well studied, in part due to the availability of target specific ?-conotoxins (?-Ctxs). In contrast, all native ?-Ctxs identified that potently block ?6?4 nAChRs exhibit higher potencies for the closely related ?6?2?3 and/or ?3?4 subtypes. In this study, we have identified a novel peptide from Conus ventricosus with pronounced selectivity for the ?6?4 nAChR. The peptide-encoding gene was cloned from genomic DNA and the predicted mature peptide, ?-Ctx VnIB, was synthesized. The functional properties of VnIB were characterized at rat and human nAChRs expressed in Xenopus oocytes by two-electrode voltage clamp electrophysiology. VnIB potently inhibited ACh-evoked currents at r?6?4 and r?6/?3?4 nAChRs, displayed ?20-fold and ?250-fold lower potencies at r?3?4 and r?6/?3?2?3 receptors, respectively, and exhibited negligible effects at eight other nAChR subtypes. Interestingly, even higher degrees of selectivity were observed for h?6/?3?4 over h?6/?3?2?3 and h?3?4 receptors. Finally, VnIB displayed fast binding kinetics at r?6/?3?4 (on-rate t½?=?0.87 min-1, off-rate t½?=?2.7 min-1). The overall preference of VnIB for ?4* over ?2* nAChRs is similar to the selectivity profiles of other 4/6 ?-Ctxs. However, in contrast to previously identified native ?-Ctxs targeting ?6* nAChRs, VnIB displays pronounced selectivity for ?6?4 nAChRs over both ?3?4 and ?6?2?3 receptors. VnIB thus represents a novel molecular probe for elucidating the physiological role and therapeutic properties of ?6?4* nAChRs.
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Project description:Primary objectives: The primary objective is to investigate circulating tumor DNA (ctDNA) via deep sequencing for mutation detection and by whole genome sequencing for copy number analyses before start (baseline) with regorafenib and at defined time points during administration of regorafenib for treatment efficacy in colorectal cancer patients in terms of overall survival (OS).
Primary endpoints: circulating tumor DNA (ctDNA) via deep sequencing for mutation detection and by whole genome sequencing for copy number analyses before start (baseline) with regorafenib and at defined time points during administration of regorafenib for treatment efficacy in colorectal cancer patients in terms of overall survival (OS).
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