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

项目摘要/摘要 烟碱型乙酰胆碱受体(NAChRs)广泛表达于中枢神经系统，调节中枢神经系统的释放 涉及学习、情绪和奖励的关键神经递质。NAChRs也存在于各种非 神经组织，包括免疫细胞、皮肤、胃肠上皮和乳腺肿瘤。在我们的研究中 由R01 GM103801和P01 GM48677项目资助的实验室专注于使能 对nAChRs如何在单细胞和系统水平上调节信号的机械性理解。毒液 来自捕食性海洋蜗牛，被称为Conus，是已知的最丰富的多样化的进化精炼的来源 靶向nAChRs的配体。我们在从这些毒液中开发多肽方面取得了实质性的进展 它们对含有α6亚单位的nAChRs亚型具有选择性。这些多肽已被广泛用于 证明特定的nAChR亚型调节关键的多巴胺能回路，这些回路与 药物的成瘾特性和运动障碍，如帕金森氏症。另外，我们 在确认α9α10nAChR作为治疗神经性疾病的新靶点方面取得了突破性进展 疼痛。我们通过开发有效和高选择性的螺杆肽，使这一进展成为可能。在接下来的5年里 多年来，我们研究计划的首要目标将是开发强大的、高度选择性的 用于研究nAChRs其他亚型的刀豆肽探针。我们将继续利用 得到的化合物在医学上的应用。一个特别的重点将是开发具有高密度的新的配体 非神经细胞nAChR亚型的特异性。在非神经细胞中表达最广泛的nAChRs 细胞有α7、α9、α10和α5亚基，我们对这些亚基的了解是有限的。我们将利用由此产生的 用于检测这些nAChR亚型的结构和功能的多肽探针。我们已经证明了 阻断α-9-α-10nAChRs在多种神经病理性疼痛动物模型中具有镇痛作用。我们非常感兴趣的是 有选择性的刀豆多肽不仅可以缓解神经病理性疼痛，而且还可以防止 加速神经损伤的恢复。因此，潜在的治疗机制具有重要的意义。 用于真正的疾病修正疗法。我们将检验nAChRs在非神经元中的调制假设 细胞是理解在创伤、化疗和治疗模型中观察到的疾病修饰的关键 糖尿病引起的神经损伤。

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.