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Conus Peptides and Their Receptor Targets: Towards Constellation Pharmacology.

圆锥肽及其受体靶标：星座药理学。

基本信息

批准号：
8740921
负责人：
BALDOMERO M OLIVERA
金额：
$ 237.69万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-01-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8740921
关键词：
Adopted Animal Disease Models Axon Biodiversity Biological Biological Assay Biomedical Research Blood Glucose Bradykinin Brain Stem Calcium Cell membrane Cells Characteristics Chemicals Chronic Clip Collaborations Communication Complement Complement Receptor Complex Cone Conotoxin Conus genus Coupled Data Dendrites Development Diagnostic Disease Progression Dissociation Electrophysiology (science)Exposure to Gene Family Genes Glucose Transporter Goals Histamine Image Individual Ion Channel Learning Ligands Link Marines Mechanics Mediating Methodology Methods Modeling Molecular Molecular Genetics Molecular Target Morphology Nature Nervous system structure Neurons Neuropharmacology Pain Pancreas Peptide Hydrolases Peptides Pharmaceutical Preparations Pharmacology Physiological Population Potassium Channel Preparation Property Protein Isoforms Protein Subunits Rattus Reading Research Role Signal Transduction Signaling Molecule Signaling Protein Slice Snail Venoms Snails Source Spinal Ganglia Staging Structure System Testing Therapeutic Time Trauma Venoms Work allodynia base cell type chemotherapy combinatorial conditioning electrical property experience insulin secretion nervous system disorder novel programs public health relevance reagent standard receptor research study respiratory response tool voltage

项目摘要

Program Summary This program uses biodiversity for basic biomedical research, with direct therapeutic and diagnostic applications. The program focuses on the discovery, characterization and development of powerful pharmacological agents targeted to signaling molecules (e.g., receptors and ion channels). The source of these are >10,000 species of venomous marine snails (particularly the cone snails, Conus). The venoms of these snail are complex, containing ca. 100 different peptides ("conopeptides, conotoxins"), each highly selective for a particular receptor or ion channel. Because of the molecular complexity of their targets, conopeptides have been particularly useful for understanding the function of molecular isoforms of these signaling molecules. Increasingly, they have become standard reagents in neuropharmacology, and serve as an essential complement to molecular genetics for understanding neuronal function and the circuitry of the nervous system. The basis of physiological circuits is chemical and electrical communication between cells, which is mediated by a vast diversity of different signaling molecules. A barrier to investigating physiological circuits is the intrinsic molecular complexity of receptors and ion channels; protein subunits encoded by gene families form multimeric complexes (most commonly tetramers or pentamers). Because of the intrinsic combinatorial nature of functional multimeric ion channel complexes, a large complement of different receptors and ion channels can be generated from a few genes. For understanding receptor and ion channel function, it is optimal to use highly selective ligands that distinguish between closely-related receptor and ion channel isoforms. Our program uses the peptides that have been evolved by venomous marine snails to interact with their prey, predators and competitors as a prime source of such highly selective ligands. It is estimated that there are over 2 million biologically active peptides in marine snail venoms, which are the basis for developing the pharmacological tools to investigate the molecular complexity of receptors and ion channels, and to define the functional roles of the vast array of receptor/ion channel isoforms. A sufficiently large number of diversely targeted conopeptides have been developed by this program to allow these to be used in combination. The primary goal is to use these conopeptide combinations to investigate the distinct complement of receptor/ion channel isoforms present in each neuronal subclass. This leads to a new paradigm for using pharmacologically active compounds, which we refer to as "Constellation Pharmacology".

项目总结