Cellular basis of motor, anti-dyskinesic and neuroprotective benefits of A2A rece

描述(申请人提供)：在过去的5年里，腺苷A2a受体(A2AR)已经成为帕金森病(PD)的主要非多巴胺能治疗靶点。这种兴奋主要来自两条线的实验和临床研究，表明A2AR拮抗剂在帕金森病中有多种潜在的好处(即证实的运动刺激、神经保护的潜力和可能的抗运动障碍)。然而，需要解决的主要知识空白是：A2AR拮抗剂单独治疗与A2AR拮抗剂与L-多巴联用治疗的分子机制，以及A2AR拮抗剂可能的抗运动障碍和神经保护作用。最重要的是，A2AR拮抗剂的多重益处是由共同的机制还是由不同的细胞作用介导的？本提案的总体目标是剖析A2AR拮抗剂在帕金森病动物模型中的多种功能(即运动刺激、可能的抗运动障碍效应和潜在的神经保护)的细胞学基础。该方案的核心假设是，A2AR拮抗剂独特的抗PD特性是由不同细胞元件中的A2ARs介导的。具体地说，A2AR拮抗剂作用于突触后纹状体神经元、突触前皮质-纹状体谷氨酸能终末和小胶质细胞，分别发挥运动兴奋、抗运动障碍和神经保护作用。我们的三个KO模型具有纹状体神经元、前脑神经元或小胶质细胞中A2AR的细胞类型特异性失活，将使我们能够研究这一假说。除了为A2AR在大脑中的整合功能提供基本的神经生物学见解外，对A2AR拮抗剂潜在不同细胞机制的剖析开启了通过靶向不同的细胞元件(纹状体苍白质、大脑皮层神经元和小胶质细胞)选择性地操纵A2AR的运动、抗运动障碍和神经保护作用的新的、真实的可能性。本研究结果将为A2AR拮抗剂在PD患者中的更好临床应用提供细胞学基础。公共卫生相关性这项建议代表了一项重大的转化研究工作，目的是通过一系列新的细胞类型特异性A2A受体基因敲除小鼠模型与选择性A2A受体拮抗剂相结合，阐明腺苷A2A受体在帕金森氏病中的多种功能的细胞基础。如果我们确定负责A2A受体拮抗剂各种作用的不同细胞群体，这将为通过靶向不同的细胞元件(如纹状体苍白质、大脑皮层神经元、小胶质细胞)选择性地操纵A2AR效应开辟新的可能性。这些结果将为改善A2AR拮抗剂在帕金森病患者中的临床应用提供细胞学基础。

DESCRIPTION (provided by applicant): During the last 5 years, the adenosine A2A receptor (A2AR) has emerged as a leading non-dopaminergic therapeutic target in Parkinson's disease (PD). This excitement came primarily from two lines of experimental and clinical investigations showing multiple potential benefits of A2AR antagonists in PD (i.e. confirmed motor stimulation, potential of neuroprotection and possible anti-dyskinesia). However, major knowledge gaps need to be addressed: the molecular mechanisms for the A2AR antagonist monotherapy versus the A2AR antagonist combined therapy with L- DOPA, and for possible anti-dyskinesic as well as neuroprotective effect of A2AR antagonists. Most importantly, are the multiple benefits by A2AR antagonists mediated by a common mechanism or distinct cellular actions? The overall goal of this proposal is to dissect out the cellular basis for the multiple functions of A2AR antagonists (i.e. motor stimulation, possible anti-dyskinesic effect and potential neuroprotection) in animal models of PD. The core hypothesis of the proposal is that the distinct anti-PD properties of A2AR antagonists are mediated by A2ARs in different cellular elements. Specifically, A2AR antagonists act at post-synaptic striatopallidal neurons, presynaptic cortico-striatal glutamatergic terminals and microglia to exert motor stimulant, anti-dyskinesic and neuroprotective effects, respectively. Our three KO models with cell-type specific inactivation of the A2AR in striatal neurons, forebrain neurons, or microglial cells will allow us to investigate this hypothesis. Beyond providing basic neurobiological insights on the integrated function of A2ARs in brain, the dissection of potential distinct cellular mechanisms of A2AR antagonists opens up new and real possibilities of selectively manipulating A2AR's motor, anti-dyskinesic and neuroprotective effects by targeting different cellular elements (striatopallidal, cerebral cortical neurons, and microglia). The results of the proposed research will provide a cellular basis for the better clinical use of A2AR antagonists in PD patients. PUBLIC HEALTH RELEVANCE This proposal represents a major translational research effort to elucidate the cellular basis for the multiple functions of adenosine A2A receptors in Parkinson's disease using a series of novel cell-type specific A2A receptor knockout mouse models in conjunction with selective A2A receptor antagonists. If we identify distinct cellular populations responsible for the various actions of A2A receptor antagonists, it will open up new possibilities for selectively manipulating A2AR effects by targeting different cellular elements (e.g. striatopallidal, cerebral cortical neurons, microglial). These results will provide a cellular basis for improved clinical use of A2AR antagonists in Parkinson's disease patients.