Alpha-Conotoxin - alpha9_alpha10 nAChRs

α-芋螺毒素 - alpha9_alpha10 nAChR

• 批准号: 7409890
• 负责人: J MICHAEL MCINTOSH
• 金额: $ 23.86万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7409890
• 关键词: Acetylcholine; Advanced Development; Affinity; Alzheimer' s Disease; Amino Acid Substitution; Amino Acids; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Binding Proteins; Binding Sites; Biological Assay; Cells; Chimera organism; Class; Cognition; Conotoxin; Data; Development; Disease; Drosophila acetylcholine receptor alpha-subunit; Drug or chemical Tissue Distribution; Electrophysiology (science); Elements; Environment; Epitopes; Face; Failure; Family; Fluorescent Probes; Funding; Gated Ion Channel; Grant; Health; Image; Immune; Immune system; Individual; Inflammatory Response; Investigation; Ion Channel; Ligand Binding; Ligands; Medicine; Modeling; Molecular; Molecular Probes; Molecular Structure; Muscle; Mutate; Mutation; Nervous system structure; Neuroglia; Neurons; Nicotinic Receptors; Numbers; Pain; Paralysed; Parkinson Disease; Pathway interactions; Peptide Synthesis; Peptides; Perception; Peripheral; Personal Satisfaction; Pharmaceutical Preparations; Physiological Processes; Play; Population; Potassium Channel; Predisposition; Principal Investigator; Process; Progress Reports; Public Health; Purpose; Range; Reporter; Resistance; Role; Schizophrenia; Sensory; Series; Site; Site-Directed Mutagenesis; Snake Venoms; Sodium Channel; Specificity; Standards of Weights and Measures; Structure-Activity Relationship; Testing; Tissues; Toxin; Translating; Venoms; Work; X-Ray Crystallography; Xenopus oocyte; alpha Bungarotoxin; alpha-Conotoxin; analog; base; chronic pain; disulfide bond; improved; member; motor control; nerve injury; novel; painful neuropathy; peptide analog; programs; receptor; therapeutic target; three dimensional structure; two-dimensional; voltage

Nicotinic acetylcholine receptors (nAChRs) regulate critical physiological processes in the nervous and immune systems. These receptors represent potential therapeutic targets for new medicines to treat disorders of motor control (e.g., Parkinson's Disease), cognition (e.g., Alzheimer's Disease and schizophrenia), and sensory perception (e.g., chronic pain). Multiple subtypes of nAChRs exist, and different subtypes of these receptors underlie the pathophsyiology of various disease states. However, the ability to pharmacologically distinguish among these subtypes has been a problem. Conotoxins are unique peptides that not only are being used to overcome this problem but also serve as powerful probes for molecular characterization of nAChRs. We will utilize a newly discovered conotoxin RgIA, which specifically targets the alpha9alpha10 subtype of nAChR, to probe the molecular structure of the receptor. This subtype has a highly restricted tissue distribution and was recently shown to participate in a molecular pathway of neuropathic pain (i.e., pain induced by nerve injury). We will identify the features of RgIA that are responsible for its selectivity and high affinity for alpha9alpha10 nAChRs. We will use this information to create a battery of ligands, including fluorescent ones, to study alpha9alpha10 nAChRs in their native tissue environment. We have also exploited conotoxins to uncover and delineate previously unrecognized binding sites on the nAChR. In this regard, Project I will continue to work closely with discovery aspects of the Program to further characterize conotoxins that act at novel sites of nAChRs. Such investigation will enable further mechanistic understanding of the nAChR in particular and is expected to translate to improved understanding of ligandgated ion channels in general. Public Health Statement: Information from this project will help characterize a class of nervous system recognition molecules that are important in health problems ranging from Parkinson's disease to chronic pain. Detailed understanding of these molecules will faciltate the development of new medications to treat these illnesses.

烟碱乙酰胆碱受体（NACHRS）调节神经和 免疫系统。这些受体代表了治疗新药物的潜在治疗靶标 运动控制障碍（例如帕金森氏病），认知（例如，阿尔茨海默氏病和 精神分裂症）和感觉知觉（例如慢性疼痛）。存在多种NACHR的亚型，并且不同 这些受体的亚型是各种疾病状态的病理学。但是，能够 从药理上区分这些亚型一直是一个问题。结合毒素是独特的肽 这不仅被用来克服这个问题，而且还可以作为分子的强大探针 NACHR的表征。我们将利用新发现的蛋白毒素RGIA，专门针对 NACHR的α9Alpha10亚型，以探测受体的分子结构。这个子类型有一个 组织分布受到严格限制，最近被证明参与了 神经性疼痛（即神经损伤引起的疼痛）。我们将确定RGIA的特征 负责其选择性和对alpha9alpha10 nachrs的高亲和力。我们将使用此信息来 创建一系列配体，包括荧光的配体，以研究其天然组织中的α9alpha10nachrs 环境。 我们还利用结合毒素来揭示和描述以前未认可的结合位点 nachr。在这方面，项目我将继续与该计划的发现方面紧密合作，以进一步 表征在NACHRS新颖部位作用的结合毒素。这样的调查将使进一步的机理 特别是对NACHR的理解，预计将转化为提高对韧带的理解 离子通道一般。 公共卫生声明：该项目的信息将有助于表征一类神经系统 识别分子在从帕金森氏病到慢性的健康问题中很重要 疼痛。对这些分子的详细理解将促进新药物的开发以治疗 这些疾病。