Anti-NMDA receptor antibodies in adult brain dsyfunction & fetal brain developmen

成人脑功能障碍中的抗 NMDA 受体抗体

• 批准号: 8741183
• 负责人: Betty Diamond
• 金额: $ 228.77万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8741183
• 关键词: Acute; Address; Adult; Affect; Anti-DNA Antibodies; Antibodies; Antigens; Apoptotic; B cell repertoire; B-Lymphocytes; Behavior; Behavioral; Binding; Blood - brain barrier anatomy; Brain; Brain Diseases; Brain Injuries; Cells; Cerebrospinal Fluid; Cessation of life; Clinical Trials; Cognitive; DNA; Data; Development; Diagnosis; Disease; Electrophysiology (science); Functional disorder; Future; Gadolinium; Glutamates; Hippocampus (Brain); Human; Hyperprolactinemia; Image; Immunocompetent; Impaired cognition; Impairment; In Vitro; Ingestion; Injury; Kinetics; Lead; Ligands; Longitudinal Studies; Lupus; Magnetic Resonance Imaging; Measures; Mediating; Mediator of activation protein; Memory; Memory impairment; Metabolic; Methodology; Methods; Metric; Microglia; Modeling; Monoclonal Antibodies; Mus; N-Methyl-D-Aspartate Receptors; Neuraxis; Neuronal Dysfunction; Neurons; Neurophysiology - biologic function; Neuropsychiatric Systemic Lupus Erythematosus; Neurosecretory Systems; Neurotransmitter Receptor; Outcome; Outcome Measure; Pathogenesis; Patients; Pituitary Gland; Positioning Attribute; Preparation; Production; Prolactin; Publishing; Quality of life; Receptor Activation; Receptor Signaling; Research Personnel; Rest; Role; Serum; Severities; Slice; Structure; Symptoms; Systemic Lupus Erythematosus; Testing; Therapeutic; Therapeutic Agents; Tissues; Veins; antibody inhibitor; autoreactive B cell; autoreactivity; base; behavioral impairment; brain tissue; burden of illness; cohort; excitatory neuron; fetal; fluorodeoxyglucose; functional disability; gadolinium oxide; immunocytochemistry; in vivo; mouse model; neuroimaging; neuron loss; neuropsychiatry; neurotoxic; neurotoxicity; novel; prevent; programs; public health relevance; receptor binding; small molecule; transcriptome sequencing

DESCRIPTION (provided by applicant): This proposal is to continue studies of a subset of anti-DNA antibodies, termed DNRAbs, that cross-react with the N-methyl-D-aspartate receptor and contribute to neuropsychiatric SLE (NPSLE). The first 5 years of the Program provided the first mechanistic model for antibody mediated injury in NPSLE, demonstrating in mice that DNRAbs could cause both cognitive and behavioral impairments. DNRAbs are present in cerebrospinal fluid (CSF) and brain tissue of patients with NPSLE and titers in CSF correlate with symptom severity. We have also developed a small molecule competitive inhibitor of antibody binding. We propose over the next 5 years to develop a model for reversible functional brain impairment as well as fixed functional impairment. In Project 1, we will determine the contribution of antibody concentration and NMDAR subunit composition to reversible and irreversible injury. We will test whether neuron loss is a prerequisite for fixed impairment or whether DNRAbs- mediated effects can lead to persistent neuronal dysfunction in its absence. We will explore the activation of microglial cells that have ingested dead neurons and their role in maintaining neuronal dysfunction. In Project 2, we will explore the potential for neuroimaging to distinguish DNRAb-mediated damage from other insults in NPSLE. We will explore progression of brain dysfunction through imaging and neuropsychiatric testing. We will develop an imaging metric to use as an outcome measure in trials of NPSLE and DNRAb blockade. In Project 3, we will begin to explore effects of DNRAbs on pituitary cells not protected by a blood brain barrier and the capacity of DNRAbs to augment prolactin production. Because prolactin levels are high in 20 to 25% of SLE patients and because prolactin leads to a more autoreactive B cell repertoire, we will test whether decoy antigens can lead to reduced serum prolactin and might perhaps lead to diminished autoreactivity. These studies derive from extensive published and preliminary data and will continue to develop paradigms for NPSLE. The coordinated study of mice and patients enriches our understanding of pathogenesis, validates our mouse model, and provides an opportunity for future testing of therapeutic agents.

描述（由申请方提供）：本提案旨在继续研究一种称为DNRAb的抗DNA抗体亚组，该抗体与N-甲基-D-天冬氨酸受体交叉反应，并导致神经精神系统性红斑狼疮（NPSLE）。该计划的前5年为NPSLE中抗体介导的损伤提供了第一个机制模型，在小鼠中证明DNRAb可引起认知和行为障碍。DNRAb存在于NPSLE患者的脑脊液（CSF）和脑组织中，CSF中的滴度与症状严重程度相关。我们还开发了一种抗体结合的小分子竞争性抑制剂。我们建议在未来5年内开发可逆性功能性脑损伤以及固定功能性脑损伤的模型。在项目1中，我们将确定抗体浓度和NMDAR亚基组成对可逆和不可逆损伤的贡献。我们将测试神经元损失是否是固定损伤的先决条件，或者DNRAbs介导的作用是否会在其缺失时导致持续的神经元功能障碍。我们将探讨已经摄取死亡神经元的小胶质细胞的激活及其在维持神经元功能障碍中的作用。 在项目2中，我们将探索神经影像学的潜力，以区分DNRAB介导的损害从其他侮辱NPSLE。我们将通过影像学和神经精神测试来探讨脑功能障碍的进展。我们将开发一种成像指标，用作NPSLE和DNRAb阻断试验的结局指标。 在项目3中，我们将开始探索DNRAbs对不受血脑屏障保护的垂体细胞的影响，以及DNRAbs增加催乳素产生的能力。因为催乳素水平在20 - 25%的SLE患者中是高的，并且因为催乳素导致更多的自身反应性B细胞库，我们将测试诱饵抗原是否可以导致血清催乳素降低，并且可能导致自身反应性降低。 这些研究来自广泛的已发表和初步的数据，并将继续发展NPSLE的范例。小鼠和患者的协调研究丰富了我们对发病机制的理解，验证了我们的小鼠模型，并为未来测试治疗药物提供了机会。