Adenosine receptor A2A regulation of EAE and CNS lymphocyte infiltration

腺苷受体 A2A 对 EAE 和 CNS 淋巴细胞浸润的调节

• 批准号: 7922131
• 负责人: Jeffrey H Mills
• 金额: $ 5.22万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922131
• 关键词: Address; Adenosine; Adenosine A2A Receptor; Adoptive Transfer; Affect; Agonist; Animal Model; Autoimmune Process; Blood; Bone Marrow; CD4 Positive T Lymphocytes; Cell Adhesion Molecules; Cell Line; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Chimera organism; Development; Disease; Disease Progression; Encephalomyelitis; Enzymes; Epithelial Cells; Experimental Autoimmune Encephalomyelitis; Fellowship; Glycosylphosphatidylinositols; Hematopoietic; Human; Immune; In Vitro; Infiltration; Inflammation; Inflammatory; Link; Lymphocyte; Mediator of activation protein; Membrane Proteins; Mission; Multiple Sclerosis; Mus; National Institute of Neurological Disorders and Stroke; Nervous system structure; Neuraxis; Paralysed; Process; Protein Dephosphorylation; Purine Nucleosides; Purinergic P1 Receptors; Receptor Signaling; Regulation; Relapse; Research; Resistance; Role; Severity of illness; Signal Transduction; Signaling Molecule; Stromal Cells; Structure of choroid plexus; Symptoms; T-Lymphocyte; Testing; Tight Junctions; Training; Wild Type Mouse; base; cell injury; cell motility; cell type; design; extracellular; human ADORA2A protein; insight; junctional adhesion molecule; migration; mouse model; nervous system disorder; prevent; repaired; research study

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.

描述（由申请人提供）：多发性硬化症（MS）是中枢神经系统（CNS）的一种自身免疫性炎症性疾病，影响了全球超过一百万的人。虽然这种使人衰弱的疾病的原因尚不清楚，但我们利用MS的实验自身免疫性脑脊髓炎（EAE）小鼠模型的研究强烈表明，嘌呤核苷腺苷及其A2A腺苷受体（AR）亚型的信号是疾病发育所需的。具体而言，我们发现缺乏细胞外腺苷催化酶，CD73或赋予阻断A2AAR信号传导的拮抗剂的小鼠受到EAE的保护。此外，我们发现CD73和A2AAR在脉络丛上高度表达，CNS结构控制着淋巴细胞从血液到CSF的通过，并已被认为是EAE/MS期间的自动诊断淋巴细胞进入CNS中CNS的切入点。我们假设脉络丛处的A2AAR信号传导是将淋巴细胞进入中枢神经系统的EAE/MS疾病进展所必需的。因此，我建议研究A2AAR信号如何调节EAE进展和淋巴细胞浸润到中枢神经系统中。具体来说，我将确定A2AAR - / - 小鼠是否容易受到EAE的影响。此外，我将使用收养转移研究来确定在淋巴细胞或中枢神经系统中是否需要A2AAR信号传导才能进行EAE进展。我将使用A2AAR拮抗剂治疗（可有效防止小鼠EAE的发展），并试图减少已经存在EAE或防止EAE复发发作的小鼠中的疾病。我还将评估A2AAR信号传导对淋巴细胞通过脉络丛处的中枢神经系统的后果。为此，我将利用A2AAR激动剂来确定是否可以诱导淋巴细胞迁移跨体外脉络丛屏障。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粘附分子的表达。我们的研究结果将提供有关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的新见解。我们的项目高度符合Ninds的使命，以减轻神经系统疾病的负担。相关性：使用动物模型进行多发性硬化症（MS），我们有证据表明腺苷受体信号传导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的发展提供基础，该疗法旨在阻止免疫细胞侵袭在神经炎症性疾病（例如MS）中的中枢神经系统中。这种疗法可用于阻止MS造成的损害的进度，甚至可能逆转。