Adenosine receptor A2A regulation of EAE and CNS lymphocyte infiltration

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统（CNS）的自身免疫性炎症性疾病，影响全球超过100万人。虽然这种使人衰弱的疾病的原因尚不清楚，但我们利用实验性自身免疫性脑脊髓炎（EAE）小鼠模型进行的MS研究强烈表明，嘌呤核苷腺苷及其A2 A腺苷受体（AR）亚型的信号传导是疾病发展所必需的。具体来说，我们发现，缺乏细胞外腺苷催化酶CD 73或给予阻断A2 AAR信号传导的拮抗剂的小鼠免受EAE的影响。此外，我们发现CD 73和A2 AAR在脉络丛上高度表达，脉络丛是控制淋巴细胞从血液到CSF的通道的CNS结构，并且已经被提出是EAE/MS期间自身反应性淋巴细胞进入CNS的入口点。我们假设脉络丛处的A2 AAR信号传导是淋巴细胞进入CNS用于EAE/MS疾病进展所必需的。因此，我建议研究A2 AAR信号如何调节EAE的进展和淋巴细胞浸润到中枢神经系统。具体来说，我将确定A2 AAR-/-小鼠是否对EAE易感。此外，我将使用过继转移研究，以确定是否A2 AAR信号是必需的淋巴细胞或中枢神经系统的EAE进展。我将使用A2 AAR拮抗剂治疗（有效预防小鼠EAE的发生），并尝试减轻已有EAE的小鼠的疾病或预防EAE复发。我还将评估A2 AAR信号对淋巴细胞通过脉络丛进入CNS的后果。为了实现这一点，我将利用A2 AAR激动剂，以确定是否可以诱导淋巴细胞迁移通过体外脉络丛屏障。此外，我将确定是否A2 AAR激动剂可以改变脉络丛上皮细胞的细胞和紧密连接粘附分子的表达。我们的研究结果将为研究正常和疾病条件下CNS淋巴细胞迁移的调节提供新的见解。我们的项目高度符合NINDS减轻神经系统疾病负担的使命。相关性：使用多发性硬化（MS）的动物模型，我们有证据表明腺苷受体信号调节淋巴细胞进入中枢神经系统（CNS）。我们的研究将为开发潜在的基于腺苷受体的治疗方法提供基础，这些治疗方法旨在阻断免疫细胞侵入神经炎性疾病（如MS）的CNS。这些治疗方法可用于阻止MS的进展，甚至可能逆转MS造成的损害。

DESCRIPTION (provided by applicant): Multiple Sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) that affects over one million people worldwide. While the cause ofthis debilitating disease is unknown, our studies utilizing the experimental autoimmune encephalomyelitis (EAE) mouse model for MS strongly suggests that the purine nucleoside adenosine and the signaling of its A2A adenosine receptor (AR) subtype are required for disease development. Specifically, we found that mice that lack the extracellular adenosine catalyzing enzyme, CD73, or that are given antagonists that block A2AAR signaling are protected from EAE. Additionally, we found that CD73 and the A2AAR are highly expressed on the choroid plexus, a CNS structure which controls the passage of lymphocytes from the blood to CSF and has been proposed to be the entry point of autoreactive lymphocytes into the CNS during EAE/MS. We hypothesize that A2AAR signaling at the choroid plexus is required for the entry of lymphocytes into the CNS for EAE/MS disease progression. Therefore, I propose to study how A2AAR signaling regulates EAE progression and lymphocyte infiltration into the CNS. Specifically, I will determine if A2AAR-/- mice are susceptible to EAE. Additionally, I will use adoptive transfer studies to determine if A2AAR signaling is required on lymphocytes or in the CNS for EAE progression. I will use A2AAR antagonist treatments (which are effective at preventing the development of EAE in mice) and attempt to lessen disease in mice that have preexisting EAE or to prevent the onset of EAE relapse. I will also evaluate the consequences of A2AAR signaling on lymphocyte passage into the CNS at the choroid plexus. To accomplish this, I will utilize A2AAR agonists to determine if the lymphocyte migration across an in vitro choroid plexus barrier can be induced. Additionally, I will determine whether A2AAR agonists can alter the expression of cellular and tight junction adhesion molecules on choroid plexus epithelial cells. The results from our studies will provide new insights into how CNS lymphocyte migration is regulated in normal and disease conditions. Our project highly conforms to the NINDS mission to reduce the burden of neurological disease. Relevance: Using the an animal model for multiple sclerosis (MS), we have evidence that adenosine receptor signaling regulates the entry of lymphocytes into the central nervous system (CNS). Our research will provide the basis for development of potential adenosine receptor based therapies aimed at blocking immune cell invasion into the CNS in neuroinflammatory diseases such as MS. Such therapies could be used to stop the progress of, or even possibly reverse the damage caused by MS.