Alpha9*-Nicotinic Receptors in Autoimmunity and Inflammation

描述(由申请人提供)：炎症性和自身免疫性疾病在个人和经济上都很昂贵，对目前的治疗方法反应不是很好。为了成功治疗这些疾病的长期目标，该项目试图确定烟碱型乙酰胆碱受体(NAChR)在这些疾病中所起的作用，特别是那些包含9个亚单位(？9*-nAChR)的受体。免疫、自主神经和中枢神经系统之间的胆碱能信号和相互作用与炎症和抗炎反应有关。我们和其他人已经证明，在多发性硬化症(MS)的实验性自身免疫性脑脊髓炎(EAE)模型中，尼古丁暴露可以预防炎症和免疫攻击。然而，对于nAChR参与抗炎或促炎反应、免疫/自身免疫以及尼古丁的免疫抑制作用，以及这些nAChR的细胞起源，我们缺乏了解。我们的初步发现表明，9*-nAChR在免疫系统中大量表达，因为那里的nAChR？9亚单位信息水平高于神经系统，可能除了耳蜗外。此外，虽然尼古丁可以预防野生型小鼠的EAE诱导，但它似乎对缺乏nAChR？9亚单位表达的小鼠没有影响。然而，9-/-小鼠发生EAE的时间模式及其严重程度与尼古丁治疗的野生型动物相似。也就是说，9*-nAChR的基因缺失或它们的药理阻断(尼古丁是9*-nAChR功能的拮抗剂，与它作为激动剂在其他 NAChR亚型)似乎对EAE也有同样的保护作用。这个探索性/发展项目将测试免疫细胞9*-nAChR发挥促炎作用并参与自身免疫反应的总体假设。一个目的是在控制条件下和在炎症反应过程中，在纯化和/或分选的外周或中央免疫细胞群体中确定nAChR？9亚单位的表达谱。另一个目的是利用结构性和条件性nAChR？9亚单位敲除小鼠来确定9*-nAChR在EAE模型中的免疫和炎症反应以及这些反应的尼古丁敏感性中的作用。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 EAE模型中的炎症和自身免疫反应中所起的作用。这将为深入了解9*-nAChR在胆碱能/尼古丁抗炎和免疫抑制效应中的关键作用提供依据。这将为进一步研究9*-nAChR的机制和检测9*-nAChR亚型选择性配体的治疗潜力奠定基础。

DESCRIPTION (provided by applicant): 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.