Nogo Receptors as Therapeutic Targets in a Model of Multiple Sclerosis

Nogo 受体作为多发性硬化症模型的治疗靶点

• 批准号: 8774166
• 负责人: Benjamin M Segal
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8774166
• 关键词: Acute; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Diseases; Autoimmune Process; Axon; Binding; Biological; Bone Marrow; Caring; Cells; Central Nervous System Diseases; Chimeric Proteins; Chronic; Clinical; Clinical Trials; Complex; Data; Demyelinations; Dendritic Cells; Development; Disease; Disease remission; Experimental Autoimmune Encephalomyelitis; Family; Fc Receptor; Frequencies; Goals; Health; Healthcare Systems; Hematopoietic; Immunoglobulins; Infiltration; Inflammation; Inflammatory; Interferon-beta; Lead; Lesion; Leukocyte Trafficking; Leukocytes; Life; Measures; Microglia; Modeling; Multiple Sclerosis; Mus; Myelin; Myeloid Cells; Neuraxis; Neuroglia; Neurologic; Neurologic Dysfunctions; Neurons; Oligodendroglia; Patients; Peripheral; Phase; Play; Property; Protein Binding; Proteins; Relapse; Role; Signal Transduction; Staging; Stem cells; Synaptic plasticity; T-Lymphocyte; Testing; Toxic effect; Treatment Efficacy; United States; United States Department of Veterans Affairs; Veterans; Work; axon injury; cell injury; chemotherapy; clinical practice; copolymer 1; disability; effective therapy; inhibitor/antagonist; macrophage; member; monocyte; natalizumab; neuroinflammation; neuron loss; neurorestoration; novel; preclinical study; prevent; receptor; relating to nervous system; remyelination; repaired; research study; therapeutic target; young adult

DESCRIPTION (provided by applicant): Multiple Sclerosis (MS), an autoimmune disease of the central nervous system (CNS), is the most common non-traumatic cause of neurological disability among young adults in the United States. Exacerbations of the disease occur when inflammatory foci form in the CNS resulting in demyelination and damage to neighboring axons. The vast majority of patients ultimately enter a progressive phase during which they gradually, but inexorably, accumulate disability. Clinical disability correlates most strongly with measures of axonal damage and neuronal loss. None of the disease modifying therapies (DMT) currently used to treat MS directly protect neurons or axons from injury or reverse damage once it occurs. Myelin associated inhibitors (MAIs), such as Nogo, MAG, and OMgp, constitute a family of proteins that bind cognate receptors (including Nogo receptors (NgRs) and paired immunoglobulin-like receptor B (PirB)) on axons to suppress neuronal sprouting and synaptic plasticity. Furthermore, engagement of LINGO-1, a component of the NgR1 signaling complex, on oligodendrocyte progenitor cells, inhibits oligodendrocyte differentiation and remyelination. More recently, NgRs have been found to play a role in inflammation. We propose that interactions between MAIs and their receptors (NgR1, NgR2, and PirB) both promote neuroinflammation and curtail neural and myelin repair in mice with experimental autoimmune encephalomyelitis (EAE), widely used as a model of MS. The specific aims of our proposal are as follows: 1) To investigate the role of the decoy receptor, NgROMNI, in the development of clinical EAE. We will test the therapeutic efficacy of NgROMNI, a newly developed Nogo receptor Fc fusion protein that blocks binding of MAIs to NgRs and PirB, in relapsing-remitting and progressive forms of EAE. In addition to the impact of NgROMNI on the clinical course, we will assess its effects on myelin and axonal integrity and autoimmune Tcell priming. 2) To determine whether MAI-PirB interactions facilitate the activation, differentiation and CNS trafficking of leukocyte subsets in myelin immunized mice. PirB, a member of the immunoglobulin superfamily expressed on monocytes and other leukocytes, was recently identified as a receptor for Nogo, MAG and OMgp. In this aim, we will test our working hypothesis that PirB signaling into myeloid cells is necessary for the clinical manifestation of EAE. Specifically, we predict that PirB deficiency or blockade will inhibit the differentiation and biological activities of peripheral dendritic cells that prime encephalitogenic T cells, as well as suppress the activities of monocytes, macrophages and activated microglia that accumulate in CNS lesions during autoimmune demyelination. 3) To characterize the effects of NgROMNI on neuronal sprouting and remyelination in mice with EAE. In order to distinguish the direct effects of NgROMNI on glial cells and axons from those on hematopoietic cells, NgROMNI will be administered after peak disease in relapsing remitting EAE (well past the establishment of neuroinflammatory infiltrates) and during chronic stages of progressive EAE. In complimentary experiments EAE will be compared in WT-->NgR-/- and WT-->WT bone marrow chimeric mice. Ultimately we hope that the results of these preclinical studies will set the stage for clinical trals of NgR decoy proteins or other MAI antagonists in MS. If successful, NgR antagonists will represent the first class of agents used to treat MS that have both anti-inflammatory and neuroprotective/ neurorestorative properties.

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) 自身免疫性疾病，是美国年轻人神经功能障碍的最常见非创伤性原因。当中枢神经系统中形成炎症灶，导致脱髓鞘和邻近轴突损伤时，疾病就会恶化。绝大多数患者最终进入进展阶段，在此期间他们逐渐但不可避免地积累残疾。临床残疾与轴突损伤和神经元损失的测量密切相关。目前用于治疗多发性硬化症的疾病修饰疗法 (DMT) 均无法直接保护神经元或轴突免受损伤或在损伤发生后逆转损伤。髓磷脂相关抑制剂 (MAIs)，例如 Nogo、MAG 和 OMgp，构成了一个蛋白质家族，可与轴突上的同源受体（包括 Nogo 受体 (NgR) 和配对免疫球蛋白样受体 B (PirB)）结合，抑制神经元萌芽和突触可塑性。此外，LINGO-1（NgR1 信号复合物的一个组成部分）与少突胶质细胞祖细胞的结合，抑制少突胶质细胞分化和髓鞘再生。最近，人们发现 NgR 在炎症中发挥作用。我们提出，MAI 与其受体（NgR1、NgR2 和 PirB）之间的相互作用都会促进患有实验性自身免疫性脑脊髓炎（EAE）小鼠的神经炎症并减少神经和髓磷脂修复，EAE 被广泛用作 MS 模型。我们提案的具体目标如下：1）研究诱饵受体NgROMNI在临床EAE发展中的作用。我们将测试 NgROMNI（一种新开发的 Nogo 受体 Fc 融合蛋白）在复发缓解型和进行性 EAE 中的治疗效果，该蛋白可阻断 MAI 与 NgR 和 PirB 的结合。除了 NgROMNI 对临床过程的影响外，我们还将评估其对髓磷脂和轴突完整性以及自身免疫 T 细胞启动的影响。 2) 确定MAI-PirB相互作用是否促进髓磷脂免疫小鼠中白细胞亚群的激活、分化和中枢神经系统运输。 PirB 是在单核细胞和其他白细胞上表达的免疫球蛋白超家族的成员，最近被鉴定为 Nogo、MAG 和 OMgp 的受体。为此，我们将检验我们的工作假设，即 PirB 信号传导至骨髓细胞对于 EAE 的临床表现是必要的。具体来说，我们预测 PirB 缺乏或阻断将抑制分化和 启动致脑炎 T 细胞的外周树突状细胞的生物活性，以及 抑制自身免疫性脱髓鞘过程中中枢神经系统病变中积累的单核细胞、巨噬细胞和活化小胶质细胞的活性。 3) 表征 NgROMNI 对 EAE 小鼠神经元萌芽和髓鞘再生的影响。为了区分 NgROMNI 对神经胶质细胞和轴突的直接影响与对造血细胞的直接影响，NgROMNI 将在复发缓解型 EAE 的疾病高峰期（远远超过神经炎症浸润的建立）和进行性 EAE 的慢性阶段施用。在补充实验中，将在 WT-->NgR-/- 和 WT-->WT 骨髓嵌合小鼠中比较 EAE。最终，我们希望这些临床前研究的结果将为 NgR 诱饵蛋白或其他 MAI 拮抗剂在 MS 中的临床试验奠定基础。如果成功，NgR 拮抗剂将代表用于治疗多发性硬化症的第一类药物，具有抗炎和神经保护/神经恢复特性。