Novel Neuronal nAChR-Targeted Peptides

新型神经元 nAChR 靶向肽

• 批准号: 6326239
• 负责人: J MICHAEL MCINTOSH
• 金额: $ 29.98万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6326239
• 关键词: Gastropoda; animal poison; calcium channel blockers; drug discovery /isolation; marine toxins; molecular cloning; neurotoxins; nicotinic receptors; peptide chemical synthesis; protein isoforms; protein structure function; receptor binding; toxicant screening

DESCRIPTION(From applicant's abstract): Nicotinic acetyicholine receptors (nAChRs) modulate the release of a number of key neurotransmitters in the central nervous system (CNS). Pharmacological manipulation of the function of these receptors may be beneficial in the treatment of a variety of disorders that impact mental health including schizophrenia, Tourette's syndrome, attention deficit hyperactivity disorder, mood disorders, Alzheimer's disease and chronic pain. Venom from carnivorous marine snails of the genus Conus are an extraordinarily rich source of compounds (cx-conotoxins) that potently and selectively target specific nAChR subtypes. The aim of this proposal is to identify and characterize compounds from these venoms that discriminate among distinct ACh-binding subunit interfaces of neuronal nAChRs. This aim will be accomplished by using receptor-based assays to track the purification of active venom compounds. Genes encoding a-conotoxins also will be cloned to isolate new toxins. Peptides identified by either approach will be biochemically characterized and synthesized. These peptides will then be fully characterized with respect to receptor subtype specificity and used to examine the subunit composition of presynaptic nAChRs that mediate the release of neurotransmitters. A major thrust of current research is to identify the subunits in the different functional channel subtypes of nAChRs and to understand their roles in health and disease. The availability of selective probes for the nAChR subtypes will greatly facilitate these efforts and provide a platform for development of medications capable of modulating specific nAChR-mediated functions in the nervous system.

描述（来自申请人摘要）： 烟碱乙酰胆碱受体（nAChR）调节许多乙酰胆碱受体的释放。 中枢神经系统（CNS）中的关键神经递质。药理 操纵这些受体的功能可能有益于 治疗各种影响心理健康的疾病，包括 精神分裂症，图雷特综合征，注意力缺陷多动症， 情绪障碍、阿尔茨海默病和慢性疼痛。 芋螺属肉食性海洋蜗牛的毒液是一种 丰富的化合物来源（CX-芋螺毒素）， nAChR亚型。这项建议的目的是确定和 从这些毒液中提取化合物， 神经元nAChRs的乙酰胆碱结合亚基界面。这一目标将是 通过使用基于受体的测定来跟踪活性物质的纯化， 毒液化合物编码α-芋螺毒素的基因也将被克隆以分离新的 毒素通过任何一种方法鉴定的肽将被生物化学地鉴定。 表征和合成。这些肽将被充分表征 关于受体亚型特异性，并用于检查亚基 突触前nAChR的组成，介导的释放 神经传递素 目前研究的一个主要方向是确定不同细胞中的亚基， nAChR的功能通道亚型，并了解它们在健康中的作用 和疾病nAChR亚型的选择性探针的可用性将 大大促进这些努力，并提供一个平台， 药物能够调节特定的nAChR介导的功能， 神经系统