Alpha9*-Nicotinic Receptors in Autoimmunity and Inflammation

炎症性和自身免疫性疾病在个人和经济上都是昂贵的，而且反应不是很快 到目前的治疗方法。为了实现成功治疗这些疾病的长期目标，该项目寻求 确定烟碱型乙酰胆碱受体(NAChR)在其中所起的作用，特别是那些含有 亚基(9*-nAChR)。胆碱能信号与免疫、自主神经和中枢之间的相互作用 神经系统与炎症和抗炎反应有关。我们和其他人 在实验中表明，接触尼古丁可以预防炎症和免疫攻击 多发性硬化(MS)的自身免疫性脑脊髓炎(EAE)模型。然而，我们的理解是 缺乏哪些特定的nAChR参与抗炎或促炎反应，在免疫/ 自身免疫，尼古丁的免疫抑制作用，以及这些nAChR的细胞来源。 我们的初步发现表明，9*-nAChR在免疫系统中大量表达，因为 NAChR？9亚单位的信息水平高于神经系统，可能除了 耳蜗骨。此外，虽然尼古丁可以预防野生型小鼠的EAE诱导，但它似乎有 对缺乏nAChR？9亚单位表达的小鼠无影响。然而，发展的时间模式 9/-小鼠的EAE及其严重程度与尼古丁治疗的野生型动物相似。也就是说，遗传的 缺失9*-nAChR或其药理阻断(尼古丁是9*-nAChR功能的拮抗剂，在 与其在其他nAChR亚型中作为激动剂的作用相反)似乎对EAE具有同样的保护作用。 这一探索性/发展项目将检验免疫细胞9*-nAChR 发挥促炎作用，并参与自身免疫反应。一个目标是定义nAChR？9 在对照条件下和在炎症反应过程中，纯化的亚基表达谱 和/或分类的外周或中枢免疫细胞群。另一个目标是使用构成和 条件性nAChR？9亚单位敲除小鼠确定9*-nAChR在免疫和炎症中的作用 在EAE模型中的反应以及这些反应的尼古丁敏感性。 我们希望获得有关9*-nAChR免疫系统分布的基本信息，并 阐明它们在MS的EAE模型中的炎症和自身免疫反应中所起的作用。 这将使我们深入了解9*-nAChR在胆碱能/尼古丁抗肿瘤中的关键作用。 炎症和免疫抑制作用。将为进一步的力学研究奠定基础。 关于9*-nAChR并检测9*-nAChR亚型选择性配体的治疗潜力。

Inflammatory and autoimmune disorders are personally and financially costly and are not very responsive to current therapies. Toward a long-term goal of successfully treating these disorders, this project seeks to identify roles in them played by nicotinic acetylcholine receptors (nAChR), specifically, those containing ¿9 subunits (¿9*-nAChR). Cholinergic signaling and interplay between the immune, autonomic and central nervous systems have been implicated in inflammatory and anti-inflammatory responses. We and others have shown that nicotine exposure protects against inflammation and immune attack in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). However, our understanding is deficient about what specific nAChR are involved in anti- or pro-inflammatory responses, in immunity/ autoimmunity, and in immunosuppressive effects of nicotine, and about the cellular origins of these nAChR. Our preliminary findings suggest that ¿9*-nAChR are richly expressed in the immune system, because nAChR ¿9 subunit message levels are higher there than in the nervous system, perhaps except for the cochlea. Moreover, whereas nicotine protects against induction of EAE in wild-type mice, it seems to have no effect in mice lacking nAChR ¿9 subunit expression. However, the temporal pattern for development of EAE and its severity in ¿9-/- mice are like those in nicotine-treated, wild-type animals. That is, genetic deletion of ¿9*-nAChR or their pharmacological block (nicotine is an antagonist of ¿9*-nAChR function, in contrast to its effects as an agonist at other nAChR subtypes) seem to be equally protective against EAE. This exploratory/developmental project will test the overarching hypothesis that immune cell ¿9*-nAChR play pro-inflammatory roles and are engaged in autoimmune responses. One aim is to define nAChR ¿9 subunit expression profiles, under control conditions and in the course of inflammatory responses, in purified and/or sorted populations of peripheral or central immune cells. Another aim is to employ constitutive and conditional nAChR ¿9 subunit knock-out mice to define roles for ¿9*-nAChR in immune and inflammatory responses in the EAE model and in nicotine sensitivity of those responses. We expect to obtain essential information about the immune system distribution of ¿9*-nAChR and to elucidate roles that they play in inflammation and autoimmune responsiveness in the EAE model of MS. This will provide insight into what seems to be critical involvement of ¿9*-nAChR in cholinergic/nicotinic anti- inflammatory and immunosuppressive effects. Foundations will be laid for further mechanistic studies concerning ¿9*-nAChR and examining the therapeutic potential of ¿9*-nAChR subtype-selective ligands.