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

描述（由申请人提供）：该提案旨在继续研究被称为DNRAbs的抗dna抗体亚群，该亚群与n -甲基- d -天冬氨酸受体发生交叉反应，并导致神经精神性SLE （NPSLE）。该计划的前5年提供了抗体介导的NPSLE损伤的第一个机制模型，在小鼠中证明DNRAbs可以引起认知和行为障碍。DNRAbs存在于NPSLE患者的脑脊液（CSF）和脑组织中，脑脊液滴度与症状严重程度相关。我们还开发了一种小分子竞争性抗体结合抑制剂。我们建议在未来5年内建立一个可逆的功能性脑损伤模型以及固定的功能性脑损伤模型。在Project 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。我们将测试神经元丢失是否是固定损伤的先决条件，或者DNRAbs介导的效应是否会在缺乏神经元的情况下导致持续的神经元功能障碍。我们将探讨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。

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.