A2A ADENOSINE RECEPTOR--A NOVEL ROLE IN NEUROPROTECTION

为了响应NIA计划公告99-049，研究目标编号18：“衰老的动物模型”，我们建议将A2 A腺苷受体功能的转基因模型应用于神经保护的研究，主要关注导致帕金森病的黑质纹状体多巴胺能神经元的变性。 最近，腺苷受体已成为调节神经系统细胞死亡的潜在靶点。 尽管腺苷受体A2 A亚型在缺血性和兴奋性脑损伤中的作用已被提出，但A2 A受体药物有限的特异性、溶解度和CNS可及性阻碍了进展。 为了克服这些药理学的局限性，并阐明这种受体在神经元细胞死亡中的作用，我们已经开发了一种互补的A2 A受体失活的转基因模型。 我们的初步研究表明，在这些A2 A受体敲除（KO）小鼠短暂局灶性缺血或暴露于MPTP（一种靶向黑质纹状体神经元的代谢毒素）后，神经毒性减弱。 我们建议在这些发现的基础上，进一步表征这些特征，并开始确定A2 A受体缺陷小鼠的神经保护机制。具体目标1旨在研究MPTP处理的A2 A KO小鼠中黑质纹状体神经元的存活和功能。 具体目标2的目的是提供试点数据的两个广泛的机制，可能介导的A2 A基因敲除小鼠的神经保护表型：突触前谷氨酸或多巴胺释放的调制，和突触后神经毒性暴露的易感性。 因此，这种A2 A受体失活的转基因模型的探索可能会提供新的洞察A2 A受体在神经元细胞死亡中的作用，并可能鼓励帕金森氏病，中风和其他疾病的老化神经系统的新的治疗策略的发展。

In response to NIA program announcement 99-049, Research Objective number 18: "Animal Models of Aging", we propose to apply a transgenic model of A2A adenosine receptor function to the study of neuroprotection, focusing primarily on the degeneration of nigrostriatal dopaminergic neurons that causes Parkinson's disease. Recently, adenosine receptors have emerged as potential targets for the modulation of cell death in the nervous system. Although a role for the A2A subtype of adenosine receptor has been suggested in ischemic and excitotoxic brain injury, the limited specificity, solubility and CNS accessibility of A2A receptor drugs have hindered progress. To overcome these pharmacological limitations and clarify the role of this receptor in neuronal cell death, we have developed a complementary transgenic model of A2A receptor inactivation. Our preliminary studies demonstrate attenuation of neurotoxicity in these A2A receptor knockout (KO) mice following transient focal ischemia or exposure to MPTP, a metabolic toxin that targets nigrostriatal neurons. We propose to build on these findings by further characterizing the features and beginning to identify the mechanisms of neuroprotection in A2A receptor-deficient mice. Specific Aim 1 seeks to investigate the survival and function of nigrostriatal neurons in MPTP-treated A2A KO mice. Specific Aim 2 is designed to provide pilot data on two broad mechanisms that may mediate the neuroprotective phenotype of A2A KO mice: presynaptic modulation of glutamate or dopamine release, and postsynaptic susceptibility to neurotoxic exposure. Thus, the exploration of this transgenic model of A2A receptor inactivation may provide new insight into the role of A2A receptors in neuronal cell death, and may encourage the development of novel therapeutic strategies for Parkinson's disease, stroke and other disorders of the aging nervous system.