Structural mechanisms of autoimmune diseases targeting cys-loop receptors

针对半胱氨酸环受体的自身免疫性疾病的结构机制

基本信息

批准号：
10864719
负责人：
Ryan E Hibbs
金额：
$ 65.94万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10864719
关键词：
3-Dimensional Address Affect Anions Antibodies Autoantibodies Autoimmune Autoimmune Diseases Autoimmune Process Autoimmune encephalitis Autoimmunity Binding Biochemistry Biological Assay Blood Cations Cell Surface Proteins Cerebrospinal Fluid Chromatography Clinical Complex Cryoelectron Microscopy Data Detection Development Disease Dysautonomias Electrophysiology (science)Encephalitis Epilepsy Epitopes Family Fc Receptor Fluorescence Foundations Glycine Receptors Human Immunoglobulin Fragments Ion Channel Gating Knowledge Laboratories Ligands Link Maps Mediating Molecular Molecular Sieve Chromatography Muscle Muscle Weakness Myasthenia Gravis Nervous System Neurons Neurotransmitter Receptor Nicotinic Receptors Pathogenesis Pathogenicity Pathology Patients Proteins Receptor Inhibition Reporting Research Resolution Resources Sampling Seizures Structure Testing Work antibody detection autoreactivity biophysical techniques crosslink design experience experimental study interest nervous system disorder neuromuscular neurotransmission novel receptor receptor binding receptor function receptor internalization repository serotonin receptor structural biology targeted treatment

项目摘要

Project Summary/Abstract Autoimmunity against neuronal receptors causes an array of diseases. Cys-loop receptors are a class of neuronal receptors targeted in autoimmune diseases including myasthenia gravis, autoimmune encephalitis, and autoimmune autonomic ganglionopathy. Myasthenia gravis is the longest studied; antibodies against the neuromuscular nicotinic acetylcholine receptor were described in 1974. Autoimmune autonomic ganglionopathy was first identified in 2000 as being associated with antibodies against the ganglionic nicotinic acetylcholine receptors. Most recently, autoimmune encephalitis was associated with antibodies against the related GABAA receptor. Mechanisms underlying autoimmune pathology are poorly understood but are often attributed to receptor cross-linking and internalization. However, other mechanisms that include direct inhibition of neurotransmission are increasingly reported. We have access to blood and cerebrospinal fluid from patients suffering from myasthenia gravis, autoimmune autonomic ganglionopathy, and autoimmune encephalitis. Here we propose to identify and clone autoimmune antibodies that target Cys-loop receptors. We will examine functional receptor inhibition by patient-derived antibodies using electrophysiology. We will produce antibody fragments to determine structures of the antibody-receptor complexes from different autoimmune diseases. These structures combined with functional interrogation will illuminate conserved and divergent mechanisms of autoimmune disease in this important protein superfamily. This work will lay the foundation for expansion to other targets of the Cys-loop receptor family and beyond.

项目概要/摘要针对神经元受体的自身免疫会导致一系列疾病。 Cys环受体是一类针对自身免疫性疾病（包括重症肌无力、自身免疫性脑炎）的神经元受体和自身免疫性自主神经节病。重症肌无力的研究时间最长。抗体针对 1974 年描述了神经肌肉烟碱乙酰胆碱受体。自身免疫自主神经神经节病于 2000 年首次被鉴定为与神经节烟碱抗体有关乙酰胆碱受体。最近，自身免疫性脑炎与抗相关GABAA受体。人们对自身免疫病理学的潜在机制知之甚少，但常常归因于受体交联和内化。然而，包括直接抑制在内的其他机制神经传递的报道越来越多。我们可以获取患者的血液和脑脊液患有重症肌无力、自身免疫性自主神经节病和自身免疫性脑炎。这里我们建议鉴定并克隆针对 Cys 环受体的自身免疫抗体。我们将检查使用电生理学通过患者来源的抗体抑制功能性受体。我们将生产抗体片段以确定来自不同自身免疫性疾病的抗体-受体复合物的结构。这些结构与功能询问相结合将阐明保守和不同的机制这个重要的蛋白质超家族中的自身免疫性疾病。这项工作将为扩大规模奠定基础 Cys 环受体家族的其他靶标及其他靶标。