The role of Kainate receptors in oligodendrocyte toxicity and EAE

描述（由申请人提供）：在这个项目中，我们将测试一个假设，即在多发性硬化症（MS）动物模型中，kainate受体（一个嗜离子性谷氨酸受体家族）的药理靶向是一种可行的治疗策略。谷氨酸受体激活有助于少突胶质细胞的兴奋性毒性变性，这种变性发生在异常髓鞘形成疾病中，如ms。少突胶质细胞及其祖细胞表达所有三种类型的嗜离子性谷氨酸受体（AMPA、kainate和NMDA亚家族），每种类型似乎在胶质兴奋性毒性模型中介导变性中发挥不同的作用。特别是，Kainate受体激活至少通过两种不同的机制产生毒性，钙介导的兴奋毒性和少突胶质细胞的补体攻击，这表明这些受体可能在MS中普遍存在的少突胶质细胞死亡中发挥重要作用。广谱AMPA/ Kainate受体拮抗剂在MS动物模型中有效，改善实验性自身免疫性脑脊髓炎（EAE）小鼠的疾病。与非竞争性NMDA受体拮抗剂联合使用时，可减少皮质少突胶质细胞缺血性损伤的生理指标。然而，AMPA和NMDA受体的抑制在临床上已被证明是有问题的。相反，海碱盐受体的亚型选择性拮抗剂在动物模型和临床前研究中耐受性良好，但尚未在ms动物模型中进行测试。此外，尚不清楚哪种亚型的海碱盐受体对少突胶质细胞兴奋毒性至关重要。这是一个特别重要的问题，因为天然盐酸盐受体的亚基组成将决定它们对选择性拮抗剂的敏感性。在这项探索性研究中，我们将首先通过使用基因靶向小鼠和选择性药理学工具确定特定受体亚基对脊髓少突胶质细胞兴奋毒性的贡献来验证我们的中心假设。其次，我们将测试实验性自身免疫性脑脊髓炎（EAE），一种多发性硬化症的小鼠模型，是否被kainate受体拮抗剂或在kainate受体敲除小鼠中减弱。这些实验将使我们能够明确地评估以海因酸盐受体为靶点是否代表了一种治疗多发性硬化症的潜在方法。在这个项目中，我们将在多发性硬化症动物模型中验证海因酸盐受体的抑制代表了一种减缓疾病进展的可行策略。盐酸盐受体包括一个响应兴奋性神经递质l -谷氨酸的蛋白家族；这些受体部分介导少突胶质细胞的兴奋性毒性死亡，少突胶质细胞是大脑中正常神经元功能所必需的胶质细胞。为了验证我们的假设，我们将利用新开发的选择性药理学药物和缺乏盐酸盐受体亚基的基因靶向小鼠。

DESCRIPTION (provided by applicant): In this project we will test the hypothesis that pharmacological targeting of kainate receptors, a family of ionotropic glutamate receptors, represents a viable therapeutic strategy in an animal model of multiple sclerosis (MS). Glutamate receptor activation contributes to excitotoxic degeneration of oligodendrocytes that occurs in diseases of aberrant myelination, such as MS. Oligodendrocytes and their progenitor cells express all three types of ionotropic glutamate receptors (AMPA, kainate, and NMDA subfamilies), with each appearing to play a distinct role in mediating degeneration in models of glial excitotoxicity. Kainate receptor activation, in particular, produces toxicity through at least two distinct mechanisms, calcium-mediated excitotoxicity and priming of oligodendrocytes to complement attack, suggesting that these receptors could play a prominent role in oligodendrocyte death prevalent in MS. Broad-spectrum AMPA/kainate receptor antagonists are efficacious in animal models of MS, ameliorating disease in mice with experimental autoimmune encephalomyelitis (EAE), and reducing physiological measures of ischemic damage in cortical oligodendrocytes when combined with non-competitive NMDA receptor antagonists. Inhibition of AMPA and NMDA receptors, however, has proven clinically problematic. In contrast, subtype-selective antagonists of kainate receptors are well tolerated in animal models and preclinical studies, but these have not been tested in animal models of MS. Furthermore, it is unclear what subtype of kainate receptors are critical for oligodendrocyte excitotoxicity. This is a particularly important question because the subunit composition of native kainate receptors will determine their sensitivity to selective antagonists. In this exploratory study, we will test our central hypothesis first by defining the contribution of specific receptor subunits to spinal oligodendrocyte excitotoxicity using gene-targeted mice and selective pharmacological tools. Secondly, we will test if progression of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, is attenuated by kainate receptor antagonists or in kainate receptor knockout mice. These experiments will enable us to definitively assess whether targeting of kainate receptors represents an approach with therapeutic potential in treatment of MS. PUBLIC HEALTH RELEVANCE In this project we will test the hypothesis that inhibition of kainate receptors represents a viable strategy for slowing disease progression in an animal model of multiple sclerosis. Kainate receptors comprise a family of proteins responding to the excitatory neurotransmitter L-glutamate; these receptors in part mediate excitotoxic death of oligodendrocytes, which are glial cells in the brain required for normal neuronal function. To test our hypothesis we will utilize newly developed selective pharmacological agents and gene-targeted mice lacking kainate receptor subunits.