Mechanisms of Neurodegeneration & Neuroprotection in EAE

神经退行性变的机制

• 批准号: 7469333
• 负责人: TANUJA CHITNIS
• 金额: $ 17.52万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7469333
• 关键词: Address; Animal Model; Applications Grants; Area; Attenuated; Axon; CD 200; Central Nervous System Degenerative Diseases; Central Nervous System Diseases; Chimeric Proteins; Chronic; Clinical; Data; Degradation Pathway; Demyelinations; Disease; Disease model; Encephalomyelitis; Enzymes; Experimental Autoimmune Encephalomyelitis; Experimental Models; Future; Genes; Goals; Immune response; In Vitro; Inflammation; Injury; Ligation; Macrophage Activation; Mediating; Mediator of activation protein; Methods; Microglia; Modeling; Multiple Sclerosis; Mus; Mutation; Myelin; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurologic; Neurons; Pathway interactions; Patients; Peripheral; Phase; Phenotype; Play; Relapse; Research Personnel; Resistance; Role; Spinal Cord; Staging; Symptoms; Testing; Toxic effect; Ubiquitin; Ubiquitination; Wallerian Degeneration; Wild Type Mouse; attenuation; axonopathy; base; chimeric gene; disability; experience; hematopoietic tissue; in vitro Model; macrophage; multicatalytic endopeptidase complex; mutant; neuronal survival; neuropathology; neuroprotection; neurotoxicity; prevent; programs; receptor

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a demyelinating and degenerative disease of the central nervous system (CNS). The majority of MS patients experience relapsing-remitting symptoms, followed by a secondary progressive phase of disease (24). Immunomodulatory therapies partially alter the disease course of MS during the relapsing-remitting phase; however the secondary progressive phase of the disease remains resistant to such treatments (25). A possible explanation for this dichotomy is that in the secondary phase of disease, the CNS has sustained irreversible damage to both myelin and axons, which can no longer be corrected by compensatory mechanisms. Several studies have recently shown that axonal damage is present in both MS and its animal model experimental autoimmune encephalomyelitis (EAE) and may contribute to fixed neurological deficits (26, 27). Thus, strategies that ameliorate axon damage may prevent chronic disability in MS. The Wlds mouse is a spontaneously occurring mutant with the unique phenotype of protection against several forms of axonal injury. The mechanisms of neuroprotection in this model is currently unknown, however likely relates to the function of the Ube4b/Nmnat chimeric gene (28). We have found that WId mice have an attenuated course of EAE, and have less axonal damage and demyelination than wild-type mice. In addition, we have found that these mice have increased expression of CD200 in the CNS during EAE, correlating with decreased accumulation of macrophages/microglia in the CNS. CD200 is known to be expressed on neurons, and ligation of its receptor CD200R is inhibitory for macrophage/microglial activation. Increased expression of CD200 in the CNS may promote neuroprotection in EAE and potentially in MS. In this revised grant application, our goals are 2 fold. Firstly, we will explore the role of CD200 in attenuating the immune response and neuropathology in the CNS. Macrophages/microglia have been implicated as the primary mediators of axonal damage and demyelination. Strategies to down-regulate their activation, particularly in the CNS may prevent chronic disability. Activation of CD200R by CD200 is 1 such strategy. In this Aim, we will study in more detail the dynamics and distribution of CD200 expression in the CNS in naive Wlds and wild-type mice, as well as during EAE. We will explore the effects of CD200R ligation on microglia and macrophage activation in vitro, and on a model of microglia-induced neurotoxicity. And lastly we will study the effects of CD200 CD200R pathway activation during the effector (chronic) as well as priming stages of EAE. Our second goal focuses on understanding the relationship of the Wlds chimeric gene and substrates such as CD200. Based on our recent preliminary results, which demonstrate decreased ubiquitination of CD200 in Wld spinal cord, we hypothesize that the Wld gene exerts its effects by altering the ubiquitin proteasome pathway (UPS) degradation of certain substrates, leading to the neuroprotective phenotype. Alterations in the UPS are responsible for several neurodegenerative diseases/models. We will explore the relationship between the chimeric protein and CD200. In addition, we will attempt to identify other substrates subject to altered ubiquitination that may play a role in axon protection in the Wlds model. Lastly, we will explore the possibility that inhibition of the UPS may reduce inflammation-mediated axonopathy. We anticipate that results from this final Aim may provide us with the basis for future studies in the role of the UPS pathway in axon-protection in EAE, and potentially in MS.

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）脱髓鞘和退行性疾病。大多数多发性硬化症患者经历复发缓解症状，随后出现继发性疾病进展期（24）。免疫调节疗法部分改变MS复发缓解期的病程；然而，这种疾病的继发性进展期仍然对这种治疗具有耐药性（25）。对这种分化的一种可能解释是，在疾病的继发性阶段，中枢神经系统对髓磷脂和轴突都有不可逆的损伤，这种损伤不能再通过代偿机制得到纠正。最近几项研究表明，轴突损伤存在于多发性硬化症及其动物模型实验性自身免疫性脑脊髓炎（EAE）中，并可能导致固定的神经功能缺陷（26,27）。因此，改善轴突损伤的策略可能会预防多发性硬化症的慢性残疾。Wlds小鼠是一种自发发生的突变体，具有独特的表型，可以抵抗几种形式的轴突损伤。该模型中的神经保护机制目前尚不清楚，但可能与Ube4b/Nmnat嵌合基因的功能有关（28）。我们发现，与野生型小鼠相比，野生型小鼠EAE病程较轻，轴突损伤和脱髓鞘较少。此外，我们发现这些小鼠在EAE期间CNS中CD200的表达增加，这与CNS中巨噬细胞/小胶质细胞的积累减少有关。已知CD200在神经元上表达，其受体CD200R的连接可抑制巨噬细胞/小胶质细胞的激活。CNS中CD200表达的增加可能促进EAE的神经保护，并可能促进ms的神经保护。首先，我们将探讨CD200在减弱免疫反应和中枢神经系统神经病理中的作用。巨噬细胞/小胶质细胞被认为是轴突损伤和脱髓鞘的主要介质。下调其激活的策略，特别是在中枢神经系统中，可以预防慢性残疾。CD200激活CD200R就是这样一种策略。在本研究中，我们将更详细地研究幼稚野生型小鼠和野生型小鼠以及EAE期间CNS中CD200表达的动态和分布。我们将探讨CD200R结扎对体外小胶质细胞和巨噬细胞活化的影响，以及对小胶质细胞诱导的神经毒性模型的影响。最后，我们将研究在EAE的效应（慢性）和启动阶段CD200 - CD200R通路激活的影响。我们的第二个目标是了解wds嵌合基因与CD200等底物的关系。基于我们最近的初步结果，我们发现Wld脊髓中CD200泛素化降低，我们假设Wld基因通过改变某些底物的泛素蛋白酶体途径（UPS）降解来发挥其作用，从而导致神经保护表型。UPS的改变是几种神经退行性疾病/模型的原因。我们将探索嵌合蛋白与CD200之间的关系。此外，我们将尝试识别可能在wds模型中轴突保护中起作用的泛素化改变的其他底物。最后，我们将探讨抑制UPS可能减少炎症介导的轴索病的可能性。我们预计，这一最终目的的结果可能为我们未来研究UPS通路在EAE和MS中轴突保护中的作用提供基础。