Glycine receptor autoantibodies and spinal disinhibition

甘氨酸受体自身抗体和脊髓去抑制

• 批准号: 432558954
• 负责人: Professorin Dr. Claudia Sommer
• 金额: --
• 依托单位: Neurologische Klinik und Poliklinik
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/432558954?language=en
• 关键词: Glycine; receptor; autoantibodies; spinal; disinhibition

Glycine receptor (GlyR) autoantibodies are associated with stiff-person syndrome and the life-threatening progressive encephalomyelitis with rigidity and myoclonus in children and adults. Recently, we found that patient IgG binds to various GlyRbeta subunits and reduces GlyR function in transfected cells. Here, we will investigate short- and long-term effects of GlyR autoantibodies on synaptic function, GlyR internalization, and GlyR ion channel function using electrophysiological measurements and super-resolution imaging techniques. We will examine novel GlyR-autoantibody targets such a presynaptic GlyRalpha or GlyRbeta. GlyR and GABAA receptor function will be studied at central synapses upon application of patient IgG using established brain stem slice preparations. Phenotypic behavioral changes will be determined after passive-transfer in mice and spinal glycinergic inhibition will be evaluated in vivo. We will identify the GlyR-autoantibody producing cells from patient blood and CSF with the aim to improve therapeutic options. With these data we expect to clarify if and how functional synaptic disruption underlies the GlyR autoantibody pathology. Based on these findings we aim to identify novel strategies for potential therapeutic intervention in GlyR autoantibody-associated diseases.

甘氨酸受体（GlyR）自身抗体与僵人综合征和危及生命的进行性脑脊髓炎（伴强直和肌阵挛）有关。最近，我们发现患者IgG结合到各种GlyR β亚基，并降低转染细胞中GlyR的功能。在这里，我们将调查短期和长期的影响，GlyR自身抗体对突触功能，GlyR内化，和GlyR离子通道功能，使用电生理测量和超分辨率成像技术。我们将研究新的GlyR-自身抗体靶点，如突触前GlyR α或GlyR β。将使用已建立的脑干切片制备物，在应用患者IgG后，在中枢突触处研究GlyR和GABAA受体功能。将在小鼠中被动转移后测定表型行为变化，并将在体内评价脊髓甘氨酸能抑制。我们将从患者血液和CSF中鉴定产生GlyR自身抗体的细胞，目的是改善治疗方案。有了这些数据，我们希望澄清功能性突触破坏是否以及如何成为GlyR自身抗体病理学的基础。基于这些发现，我们的目标是确定潜在的治疗干预GlyR自身抗体相关疾病的新策略。