Conus Peptides and Their Receptor Targets: Towards Constellation Pharmacology.

圆锥肽及其受体靶标：星座药理学。

• 批准号: 9339780
• 负责人: BALDOMERO M OLIVERA
• 金额: $ 10.79万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 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/9339780
• 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; targeted agent; tool; voltage

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".

计划摘要 该计划利用生物多样性进行基础生物医学研究，并直接进行治疗和诊断 申请。该节目专注于发现、表征和发展强大的 以信号分子(如受体和离子通道)为靶点的药理制剂。的来源 这些是10,000种有毒的海洋蜗牛(特别是锥形蜗牛，Conus)。毒液的毒液 这些蜗牛很复杂，含有大约100种不同的多肽(“螺毒素”)，每一种都很高。 对特定受体或离子通道有选择性。因为他们的目标分子的复杂性， 刀豆肽对于理解这些分子异构体的功能特别有用。 信号分子。它们越来越多地成为神经药理学的标准试剂，并作为 分子遗传学对了解神经元功能和神经回路的重要补充 神经系统。生理电路的基础是细胞之间的化学和电子通讯， 这是由各种不同的信号分子介导的。研究生理学的障碍 电路是受体和离子通道固有的分子复杂性；蛋白质亚单位由基因编码 家族形成多聚体复合体(最常见的是四聚体或五聚体)。因为内在的 功能多聚体离子通道复合体的组合性 离子通道可以由几个基因产生。为了了解受体和离子通道的功能，它 最好使用高选择性的配体，区分密切相关的受体和离子通道 异构体。我们的程序使用有毒海洋蜗牛进化出的多肽与之相互作用 它们的猎物、捕食者和竞争对手是这种高度选择性配体的主要来源。据估计， 海洋蜗牛毒液中含有200多万个生物活性多肽，是开发海洋蜗牛毒液的基础 研究受体和离子通道的分子复杂性并确定 大量受体/离子通道异构体的功能作用。数量足够多的不同的 该计划已经开发了靶向螺杆菌多肽，以允许这些多肽联合使用。这个 主要目的是利用这些螺杆肽组合来研究受体/离子的不同补体。 通道异构体存在于每个神经元亚类中。这导致了一种新的药理学使用范例 活性化合物，我们称之为“星座药理”。