Mechanisms of neurotoxicity of lupus anti-NMDAR antibodies: Electrophysiology to

狼疮抗 NMDAR 抗体的神经毒性机制：电生理学

• 批准号: 8380678
• 负责人: PATRICIO T HUERTA
• 金额: $ 38.24万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8380678
• 关键词: Address; Adverse effects; Affect; Agonist; Animal Model; Antibodies; Antigen Targeting; Antigens; Anxiety; Apoptosis; Apoptotic; Area; Autoantibodies; B-Lymphocytes; Behavior; Behavioral; Binding; Biological Assay; Biological Neural Networks; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Pathology; Brain region; Calcium; Cell Death; Cell physiology; Cells; Cessation of life; Chemicals; Chronic; Cognition; Cognitive; Cytotoxic agent; DNA; Diagnostic; Diamond; Doctor of Philosophy; Dose; Electrophysiology (science); Emotional; Event; Excitatory Postsynaptic Potentials; Exhibits; Exposure to; Extracellular Domain; Failure; Food; Functional disorder; Goals; Hippocampus (Brain); Human; Hybridomas; Hyperactive behavior; Impaired cognition; Lead; Libraries; Literature; Long-Term Depression; Long-Term Potentiation; Lupus; Lupus Erythematosus; Measures; Mediating; Memory; Metabolic; Mus; N-Methyl-D-Aspartate Receptors; Necrosis; Neurons; Neuropsychiatric Systemic Lupus Erythematosus; Pathology; Patients; Peptides; Pharmaceutical Preparations; Physiological; Process; Prosencephalon; Protocols documentation; Psychotic Disorders; Publishing; Rattus; Seizures; Series; Slice; Specificity; Spleen; Steroids; Study models; Symptoms; Synaptic Receptors; Synaptic plasticity; Syndrome; Systemic Lupus Erythematosus; Technology; Testing; Therapeutic; Thrombosis; Toxic effect; Whole-Cell Recordings; Work; aspartate receptor; base; combinatorial; ds-DNA; excitotoxicity; experience; extracellular; fetal; improved; in vivo; mRNA Differential Displays; memory process; microorganism antigen; mouse model; neuron loss; neuropsychiatry; neurotoxic; neurotoxicity; novel; peripheral blood; programs; receptor; receptor binding; response

Project 1: "Mechanisms of neurotoxicity of lupus anti-NMDAR antibodies: Electrophysiology to Behavior" (Huerta PI). The objective of this project is to examine whether key syndromes of neuropsychiatric lupus erythematosus (NPSLE) are caused by autoantibodies that bind the NR2A and NR2B subunits of the N-methyl-o-aspartate receptor (NMDAR). This synaptic receptor is highly expressed in forebrain neurons and is crucially involved in synaptic plasticity, which is regarded as the cellular process underlying memory storage. However, hyperactivity of the NMDAR can trigger excitotoxic effects. Our hypothesis is that certain antibodies function as partial agonists while others function as antagonists for the NMDAR, depending on the mode of interaction with the NR2A and NR2B subunits. Chronic exposure to the anti-NMDAR antibodies would lead to homeostatic imbalance and eventual death of the NMDAR-containing neurons. We aim to determine the toxic potential of a battery of murine and human anti-NMDAR antibodies, the latter having been selected either from a combinatorial library generated from spleen cells of a lupus patient or directly from antigenspecific peripheral blood B cells of three additional patients. We will expand our existing panel by isolating new human, anti-NMDAR antibodies. We will study the mechanisms by which the anti-NMDAR antibodies alter the physiological responses of the NMDAR in neurons of the hippocampus, a brain region critically targeted in NPSLE. Furthermore, we will determine the deleterious effects of the anti-NR2 antibodies over synaptic plasticity in the hippocampus. Finally, we will study the effects of anti-NMDAR antibodies on behaving mice performing a series of cognitive tasks that depend on the integrity of NMDAR-rich brain regions. Thus, we will examine how autoantibodies affect the brain, from the cellular to the behavioral level. Overall, we believe these studies will allow us to determine the functional mechanisms by which the antiNMDAR antibodies cause their neurotoxic effect in the brain. Moreover, we will gain an understanding of the effect of the anti- NMDAR antibodies on the synaptic plasticity processes that underlie memory processing. We foresee that these studies might be relevant for therapeutic protocols in NPSLE.

项目1：“狼疮抗NMDAR抗体的神经毒性机制：电生理学行为” （Huerta PI）. 本项目的目的是检查神经精神性红斑狼疮（NPSLE）的关键综合征是否 由结合N-甲基-o-天冬氨酸受体（NMDAR）的NR 2A和NR 2B亚基的自身抗体引起。这 突触受体在前脑神经元中高度表达，并在突触可塑性中起关键作用， 被认为是记忆储存的细胞过程。然而，NMDAR的过度活跃可以触发 兴奋性毒性作用我们的假设是，某些抗体作为部分激动剂发挥作用，而另一些抗体作为部分激动剂发挥作用。 NMDAR的拮抗剂，这取决于与NR 2A和NR 2B亚基的相互作用模式。慢性暴露 抗NMDAR抗体的作用会导致体内平衡失衡，并最终导致含NMDAR的细胞死亡。 神经元 我们的目的是确定一组鼠和人抗NMDAR抗体的潜在毒性，后者已经被证实是一种抗NMDAR抗体。 选自狼疮患者脾细胞产生的组合文库或直接选自抗原特异性 另外三名患者的外周血B细胞。我们将通过隔离新的 人抗NMDAR抗体。我们将研究抗-NMDAR抗体改变细胞凋亡的机制。 NMDAR在海马神经元中的生理反应，海马是NPSLE中关键靶向的脑区域。 此外，我们将确定抗NR 2抗体对突触可塑性的有害作用， 海马体。最后，我们将研究抗NMDAR抗体对小鼠行为的影响， 认知任务依赖于NMDAR丰富的大脑区域的完整性。因此，我们将研究自身抗体如何 影响大脑，从细胞到行为层面。 总之，我们相信这些研究将使我们能够确定抗NMDAR的功能机制， 抗体会在大脑中产生神经毒性作用。此外，我们还将了解反- NMDAR抗体对记忆处理基础的突触可塑性过程的影响。 我们预见这些研究可能与NPSLE的治疗方案有关。