EXPERIMENTAL AUTOIMMUNE AUTONOMIC NEUROPATHY

实验性自身免疫性自主神经病

• 批准号: 6629244
• 负责人: STEVEN A VERNINO
• 金额: $ 13.08万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-19 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629244
• 关键词: acetylcholine; active immunization; autoantibody; autoimmunity; autonomic ganglion; autonomic nervous system; disease /disorder model; electrophysiology; familial dysautonomia; human tissue; humoral immunity; immunocytochemistry; immunoglobulins; immunoprecipitation; laboratory mouse; laboratory rat; model design /development; myasthenia gravis; nervous system disorder; neural transmission; neurons; neurophysiology; neurotransmitter receptor; phenotype; tissue /cell culture

DESCRIPTION (Adapted from the Applicant's Abstract): The discovery of acetylcholine receptor (AChR) antibodies in patients with myasthenia gravis (MG) led to recognition of other IgG-mediated neurologic diseases and had practical implications for serological diagnosis and immunomodulatory therapy of MG, the Lambert-Eaton myasthenic syndrome and other disorders. Our recent serological studies have implicated autoantibodies against the neuronal AChR in autonomic ganglia as the cause of acquired severe dysautonomia in some patients. In addition, these ganglionic AChR antibodies are proving to be useful serological markers of subacute autonomic neuropathy. Serum ganglionic AChR antibody levels correlate significantly with the severity of autonomic dysfunction, and a reduction in antibody level correlates with improvement in clinical and laboratory indices of autonomic function. As part of a program to nurture the career of a young neurologist clinician-investigator, we propose to develop and study animal models of autoimmunity against the ganglionic AChR to establish the etiology of human subacute autonomic neuropathy. Initial rodent experiments will examine indices of ganglionic synaptic transmission in vitro and autonomic function in vivo. Using these studies as a baseline, subsequent experiments will evaluate the effects of passive ganglionic AChR antibody transfer and active immunization on autonomic function in animals. This project is the first step toward complete understanding of a serious human neurologic disease and lays the foundation for investigating other disorders of neuronal cholinergic transmission. Novel therapeutic trials are anticipated as a clinical translational outcome of this research. The proposed project involves close interaction with established mentors at an institution with a record of excellence in clinically-relevant basic science research. The candidate has already shown potential for independent patient-based laboratory research, and with further training will develop a successful independent research program including clinically based laboratory research and translational clinical research in neurology.

描述（根据申请人的摘要改编）：发现 疗程疗程疗程的乙酰胆碱受体（ACHR）抗体 （mg）导致认识到其他IgG介导的神经系统疾病，并患有 对血清学诊断和免疫调节治疗的实际意义 MG，兰伯特 - 伊顿肌无力综合征和其他疾病。我们最近 血清学研究暗示了针对神经元ACHR的自身抗体 自主神经节是某些人获得严重动力障碍的原因 患者。此外，这些神经节ACHR抗体被证明是 亚急性自主神经病的有用血清学标记。血清神经节 ACHR抗体水平与自主神经的严重程度显着相关 功能障碍，抗体水平的降低与改善相关 自主功能的临床和实验室指数。 作为培育年轻神经科医生职业的计划的一部分 临床医生评论者，我们建议开发和研究 对神经节的自身免疫性建立人类的病因 亚急性自主神经病。最初的啮齿动物实验将检查索引 在体内体外和自主功能的神经节突触传播的体内。 将这些研究作为基线，随后的实验将评估 被动神经节ACHR抗体转移和主动免疫对 动物的自主功能。这个项目是迈向完成的第一步 了解严重的人类神经疾病，并为 研究神经元胆碱能传播的其他疾病。小说 预计治疗试验将作为临床翻译结果 研究。 拟议的项目涉及与已建立的导师的密切互动 具有卓越临床相关的基础科学的卓越记录的机构 研究。候选人已经显示出独立的潜力 基于患者的实验室研究，并进一步培训将发展 成功的独立研究计划，包括基于临床的实验室 神经病学研究与翻译临床研究。