Development and Application of Nicotinic Acetylcholine Receptor Targeted Peptides for Biomedical Research

烟碱乙酰胆碱受体靶向肽在生物医学研究中的开发及应用

• 批准号: 10550213
• 负责人: J MICHAEL MCINTOSH
• 金额: $ 44.99万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10550213
• 关键词: Acceleration; Analgesics; Animal Model; Biomedical Research; Cells; Conus genus; Development; Diabetes Mellitus; Disease; Funding; Goals; Immune; Laboratories; Learning; Ligands; Mammary Neoplasms; Medicine; Modeling; Modification; Moods; Movement Disorders; Neuroglia; Neurotransmitters; Nicotinic Receptors; Parkinson Disease; Peptides; Pharmaceutical Preparations; Property; Recovery; Research; Resources; Rewards; Signal Transduction; Site; Skin; Snails; Source; Specificity; Structure; System; Testing; Therapeutic; Tissues; Trauma; Venoms; chemotherapy; gastrointestinal epithelium; insight; interest; marine; nerve injury; novel; painful neuropathy; prevent; programs

Project Summary/Abstract Nicotinic acetylcholine receptors (nAChRs) are broadly expressed in the CNS where they modulate the release of key neurotransmitters involved in learning, mood, and reward. nAChRs are also found in diverse non- neuronal tissues including immune cells, skin, gastro-intestinal epithelium and breast tumors. Research in our laboratory, which has been funded by R01 GM103801 and a project of P01 GM48677, is focused on enabling mechanistic understanding of how nAChRs regulate signaling at the single cell and systems levels. Venoms from predatory marine snails, known as Conus, are the richest known source of diverse, evolutionarily-refined ligands that target nAChRs. We have made substantial progress in developing peptides from these venoms that are selective for α6 subunit-containing subtypes of nAChRs. These peptides have been widely used to demonstrate that specific nAChR subtypes modulate key dopaminergic circuits that are strongly implicated in the addictive properties of drugs and in movement disorders such as Parkinson’s disease. Separately, we made groundbreaking progress in validating the α9α10 nAChR as a novel target for treatment of neuropathic pain. We enabled such progress by developing potent and highly selective conopeptides. Over the next 5 years, an overarching goal of our research program will be to develop robust suites of potent, highly selective conopeptide-based probes for the study of additional subtypes of nAChRs. We will continue to exploit the resulting compounds for applications in medicine. A particular focus will be to develop new ligands with high specificity for nAChR subtypes of non-neuronal cells. The most widely expressed nAChRs in non-neuronal cells have α7, α9, α10 and α5 subunits where our insight into function is limited. We will utilize the resulting peptide probes to examine the structures and functions of these nAChR subtypes. We have demonstrated that block of α9α10 nAChRs is analgesic in multiple animal models of neuropathic pain. Of high interest to us, is that selective conopeptides not only alleviate neuropathic pain, but they also prevent development of, or accelerate recovery from, nerve injury. Thus, the underlying therapeutic mechanism has significant implications for truly disease-modifying therapies. We will test the hypothesis that modulation of nAChRs in non-neuronal cells is key to understanding disease modification observed in models of trauma-, chemotherapy- and diabetes-induced nerve injury.

项目总结/摘要 烟碱型乙酰胆碱受体（nAChR）在CNS中广泛表达，在CNS中它们调节 学习、情绪和奖赏的关键神经递质。nAChR也存在于多种非 神经元组织，包括免疫细胞、皮肤、胃肠上皮和乳腺肿瘤。在我们的研究 该实验室由R 01 GM 103801和P01 GM 48677项目资助，重点是使 nAChRs如何在单细胞和系统水平上调节信号传导的机制理解。毒液 来自肉食性海洋蜗牛，被称为芋螺，是最丰富的已知来源， 靶向nAChRs的配体。我们在从这些毒液中开发肽方面取得了实质性进展 对含有α6亚基的nAChR亚型具有选择性。这些肽已被广泛用于 表明特定的nAChR亚型调节关键的多巴胺能回路， 药物的成瘾性和运动障碍，如帕金森氏病。另外，我们 在验证α9α10 nAChR作为治疗神经病变的新靶点方面取得了突破性进展， 痛苦我们通过开发有效且高度选择性的锥形肽实现了这一进展。在未来5 多年来，我们的研究计划的首要目标将是开发强大的套件， 用于研究nAChR的其他亚型的基于锥肽的探针。我们将继续利用 所得化合物用于医药。一个特别的重点将是开发新的配体与高 对非神经元细胞的nAChR亚型的特异性。在非神经元细胞中最广泛表达的nAChRs 细胞有α7、α9、α10和α5亚基，我们对这些亚基的功能了解有限。我们将利用由此产生的 肽探针来检查这些nAChR亚型的结构和功能。我们已经证明 阻断α9α10 nAChR在多种神经性疼痛动物模型中具有镇痛作用。我们非常感兴趣的是 选择性芋螺肽不仅可以减轻神经性疼痛，而且还可以防止神经性疼痛的发展， 加速神经损伤的恢复因此，潜在的治疗机制具有重要意义 真正的疾病缓解疗法。我们将检验非神经元细胞中nAChRs的调节 细胞是理解在创伤、化疗和 糖尿病引起的神经损伤