Modeling variable outcomes of antibody exposure

对抗体暴露的可变结果进行建模

• 批准号: 9294931
• 负责人: BRUCE Thomas VOLPE
• 金额: $ 69.39万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9294931
• 关键词: Active Immunization; Acute; Adult; Affect; Anti-DNA Antibodies; Antibodies; Apoptotic; Autoantibodies; Binding; Blood - brain barrier anatomy; Brain; Brain Diseases; Brain Injuries; Brain Pathology; Cathepsins; Cell Death; Cells; Cerebrospinal Fluid; Complement; Consensus Sequence; DNA; Data; Electrophysiology (science); Enzymes; Epitopes; Etiology; Event; Excitatory Postsynaptic Potentials; Exposure to; Extracellular Matrix; Fc Receptor; Functional disorder; Genomics; Goals; Hippocampus (Brain); Histologic; Human; Immunization; Impaired cognition; Impairment; Inbred BALB C Mice; Infection; Injury; Lead; Lipopolysaccharides; Long-Term Potentiation; Lupus; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Memory; Memory impairment; Methodology; Microglia; Mitochondria; Modeling; Monitor; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Neuropsychiatric Systemic Lupus Erythematosus; Outcome; Patients; Penetration; Peptides; Phagocytes; Phagocytosis; Physiological; Physiology; Positioning Attribute; Positron-Emission Tomography; Preparation; Process; Property; Quality of life; Reporting; Serum; Slice; Stress; Synapses; Systemic Lupus Erythematosus; Therapeutic; Tissues; Work; base; behavior test; behavioral impairment; brain metabolism; chemokine; chemokine receptor; cognitive function; cognitive testing; cross reactivity; cytokine; fetal; glucose metabolism; immunocytochemistry; in vitro Assay; in vivo; in vivo Model; injured; microPET; migration; mouse model; neuron apoptosis; neuron loss; neuropsychiatry; neurotoxic; novel; prevent; spatial memory; symptomatology; therapeutic evaluation; therapeutic target; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT - PROJECT 1 This project will further our studies of the contribution of cross-reactive anti-DNA anti-N- methyl-D-aspartate receptor (NMDAR) antibodies, denoted DNRAbs, to neuropsychiatric lupus (NPSLE). NPSLE affects approximately 80% of lupus patients and substantially diminishes quality of life. We previously pioneered models for DNRAb-mediated fixed cognitive or behavioral impairment; we will now develop a model of DNRAb-mediated transient impairment. Based on our observation of variable DNRAb concentration in cerebrospinal fluid of lupus patients, we will explore the concentration of tissue-penetrating antibody in reversible and irreversible damage. We will explore the contribution of NMDAR subunit composition to reversible and irreversible damage and will determine whether there can be irreversible injury in the absence of neuronal death. We propose the highly novel hypothesis that microglia are altered in NPSLE as a consequence of ingesting apoptotic neurons and microglial activation functions to sustain neuronal damage. Finally, we will explore therapeutic strategies for preventing irreversible brain injury. These studies will develop new paradigms for antibody-mediated brain disease. We will utilize standard methodologies such as electrophysiology in hippocampal slice preparation, behavioral and cognitive testing and immunocytochemistry. We will pioneer the use of in vivo electrophysiology, microPET studies in a mouse model of NPSLE and RNA-seq of microglial cells.

项目摘要/摘要 - 项目 1 该项目将进一步研究交叉反应性抗 DNA 抗 N- 的贡献 甲基-D-天冬氨酸受体 (NMDAR) 抗体，表示为 DNRAbs， 神经精神狼疮（NPSLE）。 NPSLE 影响大约 80% 的狼疮患者 并大大降低生活质量。我们之前开创了以下模型： DNRAb 介导的固定认知或行为障碍；我们现在将开发一个模型 DNRAb 介导的短暂损伤。根据我们对变量的观察 狼疮患者脑脊液中 DNRAb 浓度，我们将探讨 可逆和不可逆损伤中组织穿透抗体的浓度。我们 将探索 NMDAR 亚基组成对可逆和 不可逆转的损害，并决定是否存在不可逆转的伤害 没有神经元死亡。我们提出了一个非常新颖的假设：小胶质细胞是 由于摄入凋亡神经元和小胶质细胞，NPSLE 发生改变 激活功能以维持神经元损伤。最后，我们将探索治疗方法 预防不可逆脑损伤的策略。这些研究将开发新的 抗体介导的脑疾病的范例。 我们将利用标准方法，例如海马切片中的电生理学 准备、行为和认知测试以及免疫细胞化学。我们将 率先在小鼠模型中使用体内电生理学、microPET 研究 小胶质细胞的 NPSLE 和 RNA-seq。