EXPERIMENTAL AUTOIMMUNE AUTONOMIC NEUROPATHY

描述(改编自申请人的摘要)：发现 重症肌无力患者的乙酰胆碱受体抗体 (Mg)导致对其他免疫球蛋白介导的神经系统疾病的识别 血清学诊断和免疫调节治疗的实际意义 MG、Lambert-Eaton肌无力综合征等疾病。我们最近 血清学研究表明，抗神经元AChR的自身抗体在 自主神经节是获得性严重自主神经障碍的原因 病人。此外，这些神经节细胞AChR抗体被证明是 亚急性自主神经病的有用的血清学标志物。血清神经节细胞 Achr抗体水平与自主神经的严重程度显著相关 功能障碍，抗体水平的降低与疾病的改善有关 自主神经功能的临床和实验室指标。 作为一项培养年轻神经科医生职业生涯的计划的一部分 临床医生-研究人员，我们建议开发和研究动物模型 神经节细胞乙酰胆碱受体自身免疫建立人类病因学 亚急性自主神经病变。最初的啮齿动物实验将检查指数 体外的神经节突触传递和体内的自主神经功能。 以这些研究为基准，后续的实验将评估 神经节细胞AChR抗体被动转移和主动免疫对小鼠免疫功能的影响 动物的自主神经功能。这个项目是迈向完成的第一步。 了解一种严重的人类神经系统疾病，并为 研究神经元胆碱能传递的其他障碍。小说 治疗试验预计将作为这一结果的临床转化结果 研究。 拟议的项目涉及与现有的导师在 在与临床相关的基础科学方面拥有卓越记录的机构 研究。这位候选人已经显示出独立的潜力。 以患者为基础的实验室研究，并通过进一步的培训将开发出一种 成功的独立研究计划，包括以临床为基础的实验室 神经学研究和转化性临床研究。

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.