Defining the epitope in anti-AMPA receptor encephalitis

抗 AMPA 受体脑炎表位的定义

基本信息

批准号：
8427916
负责人：
DAVID ROBINSON LYNCH
金额：
$ 25.13万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8427916
关键词：
AMPA Receptors Acids Address Amnesia Antibodies Biological Models Cell surface Cells Chimeric Proteins Clinical Collaborations Data Degenerative Disorder Diagnosis Disease Encephalitis Epitopes Etiology Evaluation Event Excision Functional disorder Gene Expression Gerda brand of difluprednate Glutamate Receptor Glutamates Heterogeneity Immune System Diseases Immune response In Vitro Individual Investigation Lead Learning Link Mediating Memory Loss Modeling N-Methyl-D-Aspartate Receptors Neoplasms Neuraxis Neurologic Dysfunctions Neurons Pathogenesis Patients Plasmapheresis Play Process Protein Region Role Sampling Screening procedure Seizures Serum Site Subgroup Symptoms Synapses Synaptic Transmission Synaptic plasticity Syndrome Testing base clinical phenotype cohort crosslink extracellular immunocytochemistry immunogenicity immunoreactivity improved neuropsychiatry novel therapeutic intervention prevent receptor receptor internalization research study tool trafficking tumor

项目摘要

DESCRIPTION (provided by applicant): Glutamate, the major excitatory transmitter in the central nervous system, is crucial not only for synaptic transmission but also for long-term neuronal changes such as synaptic plasticity and control of gene expression. Many of the actions of glutamate are exerted through a specific receptor, the N-methyl-D- aspartate receptor (NMDAR), which controls the trafficking of a second glutamate receptor, the a-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR). Recently, in collaboration with Dr. Josep Dalmau, we identified two distinct encephalitic syndromes, associated directly with antibodies to NMDAR in one syndrome and with antibodies to the AMPAR in the other. In antiAMPAR encephalitis, subjects present with symptomatology (amnesia, seizures) analogous to that predicted to occur with AMPAR hypofunction. However, the syndrome can be treated in some individuals by tumor removal or plasmapheresis, suggesting that it is mediated directly by antibodies. Patients with this syndrome make antibodies to the extracellular portion of the AMPAR subunits GluR1 and/or GluR2. Our new preliminary data have identified structural determinants in the amino terminal domain (ATD) of GluR1/2 that are necessary for immunoreactivity to patients' antiAMPAR antibodies. We have also used fusion proteins from these regions to demonstrate diversity in the immune response and to identify individuals with possible antiAMPAR encephalitis who tested negatively by previous approaches. In this proposal we will continue to create new tools for investigation of patients' antiAMPAR antibodies in order to assess whether this syndrome is dramatically under diagnosed, and to link the pathophysiology to specific AMPAR portions First, we will test for the presence of antiAMPAR antibodies and antibodies to specific structural determinants on the AMPAR in samples from a large cohort of individuals with potential encephalitis. We will then correlate the results with clinical features of the subjects and determine whether pathophysiological mechanisms in anti AMPAR encephalitis are mediated through specific epitopes. Cumulatively, completion of these aims will lead to improved understanding of the pathophysiological mechanisms in this disorder, develop tools for further exploration of the mechanisms, and potentially allow creation of novel therapeutic approaches for antiAMPAR encephalitis. PUBLIC HEALTH RELEVANCE: The proposal addresses the mechanisms by which antibodies cause neurological dysfunction in the disorder known as anti-AMPA receptor encephalitis. Through understanding of this process, the proposal may facilitate therapies for preventing damage in this disorder and other forms of encephalitis. It will also provide tools to investigate mechanisms of memory loss in people.

描述（由申请人提供）：中枢神经系统中的主要兴奋性发射器谷氨酸不仅对突触传播至关重要，而且对于长期神经元变化（例如突触可塑性和基因表达的控制）至关重要。谷氨酸的许多作用都是通过特定的受体N-甲基-D-天冬氨酸受体（NMDAR）施加的，该受体控制了第二个谷氨酸受体A-Amino-3-羟基-5-羟基-5-甲基-4-甲基-4-甲式硫代促毒素酸受体（AMPAR）的运输。最近，与Josep Dalmau博士合作，我们确定了两种不同的脑综合症，与一种综合征中的NMDAR抗体直接相关，另一种综合征与AMPAR的抗体有关。在抗安邦脑炎中，具有类似于AMPAR功能低下的受试者（健忘症，癫痫发作）。但是，该综合征可以通过去除肿瘤或血浆置换在某些个体中治疗，这表明它是由抗体直接介导的。该综合征患者对AMPAR亚基1和/或GlUR2的细胞外部分产生抗体。我们的新初步数据已经确定了GLUR1/2的氨基末端结构域（ATD）中的结构决定因素，这对于对患者抗体抗体的免疫反应性是必需的。我们还使用了这些区域的融合蛋白来证明免疫反应中的多样性，并确定患有抗血症脑炎的个体，他们通过以前的方法进行了负面测试。在这项建议中，我们将继续创建新的工具，以研究患者的抗体抗体，以评估该综合征是否被诊断出很大，并将病理生理学与特定的AMPAR部分联系起来，我们将测试我们的抗体抗体和抗体的存在，并在大型组合中具有特定的AMPAR抗体，这些抗体是在大型组合中的特定造成剂中的par，该抗体是在大型组合中的特定抗体。然后，我们将将结果与受试者的临床特征相关联，并确定抗AMPAR脑炎中的病理生理机制是否是通过特定表位介导的。累积地，这些目标的完成将提高人们对这种疾病中病理生理机制的了解，开发用于进一步探索机制的工具，并有可能允许创建新型的抗血症脑炎治疗方法。公共卫生相关性：该提案解决了抗体在称为抗AMPA受体脑炎的疾病中引起神经功能障碍的机制。通过了解这一过程，该提案可以促进预防这种疾病和其他形式的脑炎损害的疗法。它还将提供研究人中记忆力丧失机制的工具。