Adenosine receptor A2A regulation of EAE and CNS lymphocyte infiltration

描述(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100多万人。虽然这种衰弱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A2A腺苷受体(AR)亚型的信号是疾病发展所必需的。具体地说，我们发现缺乏细胞外腺苷催化酶CD73的小鼠，或者给予阻断A2AAR信号的拮抗剂的小鼠，可以免受EAE的影响。此外，我们发现CD73和A2AAR在脉络丛高表达，脉络丛是一种中枢神经系统结构，控制着淋巴细胞从血液到脑脊液的通道，并被认为是EAE/MS期间自身反应性淋巴细胞进入CNS的入口点。我们推测，脉络丛上的A2AAR信号是淋巴细胞进入CNS参与EAE/MS疾病进展所必需的。因此，我建议研究A2AAR信号如何调控EAE进展和淋巴细胞向中枢神经系统的渗透。具体地说，我将确定A2AAR-/-小鼠是否对EAE易感。此外，我将使用采用转移研究来确定EAE进展是否需要淋巴细胞或中枢神经系统中的A2AAR信号。我将使用A2AAR拮抗剂治疗(在小鼠中有效地防止EAE的发展)，并试图减轻先前存在EAE的小鼠的疾病或防止EAE复发。我还将评估A2AAR信号对脉络丛处淋巴细胞进入中枢神经系统的影响。为了做到这一点，我将利用A2AAR激动剂来确定是否可以诱导淋巴细胞在体外脉络丛屏障上迁移。此外，我将确定A2AAR激动剂是否可以改变脉络丛上皮细胞上细胞和紧密连接黏附分子的表达。我们的研究结果将为在正常和疾病条件下如何调节中枢神经系统淋巴细胞迁移提供新的见解。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：利用多发性硬化症(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疗法提供基础，旨在阻止MS等神经炎性疾病中免疫细胞对中枢神经系统的入侵。此类疗法可用于阻止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.