Modeling variable outcomes of antibody exposure

对抗体暴露的可变结果进行建模

基本信息

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
项目类别：
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

项目摘要

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，至神经精神狼疮（NPSLE）。 NPSle影响大约80％的狼疮患者并大大降低了生活质量。我们以前开创了模型 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介导的瞬时损伤。根据我们对可变的观察 DNRAB浓度在狼疮患者的脑脊液中，我们将探索可逆性和不可逆损伤中组织渗透抗体的浓度。我们将探讨NMDAR亚基组成对可逆和不可逆转的损害，并将确定在缺乏神经元死亡。我们提出了一个高度新颖的假设，即小胶质细胞是由于摄入凋亡神经元和小胶质细胞而改变了NPSLE 激活功能以维持神经元损伤。最后，我们将探索治疗防止不可逆转的脑损伤的策略。这些研究将发展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制备，行为和认知测试和免疫细胞化学。我们将先锋使用体内电生理学，在小鼠模型中的微型研究小胶质细胞的NPSL和RNA-SEQ。