EXPERIMENTAL AUTOIMMUNE AUTONOMIC NEUROPATHY

描述（改编自申请人的摘要）： 重症肌无力患者乙酰胆碱受体抗体的检测 (MG)导致对其他IgG介导的神经系统疾病的认识， 血清学诊断和免疫调节治疗的实际意义 MG，Lambert-Eaton肌无力综合征和其他疾病。我们最近 血清学研究表明， 自主神经节是某些人获得性严重自主神经功能障碍的原因 患者此外，这些神经节AChR抗体被证明是 亚急性自主神经病变的有用血清学标志物。血清神经节的 AChR抗体水平与自主神经病变的严重程度显著相关， 功能障碍，抗体水平的降低与改善相关， 自主神经功能的临床和实验室指标。 作为培养年轻神经科医生事业计划的一部分 临床研究者，我们建议开发和研究动物模型， 针对神经节AChR的自身免疫，以建立人类 亚急性自主神经病变最初的啮齿动物实验将检查指标 体外神经节突触传递和体内自主神经功能。 使用这些研究作为基线，随后的实验将评估 被动神经节AChR抗体转移和主动免疫对 动物的自主神经功能这个项目是完成的第一步 了解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疾病。小说 预期治疗试验将作为这一研究的临床转化结果。 research. 拟议的项目涉及与既定导师在一个 在临床相关基础科学方面成绩卓越的机构 research.这位候选人已经显示出独立的潜力。 以病人为基础的实验室研究，并与进一步的培训将制定一个 成功的独立研究项目，包括临床实验室 神经病学的临床研究和转化研究。

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.