Experimental Dysautonomia: Pathogenesis and Treatment

描述（由申请人提供）：自身免疫性自主神经病变（AAN）患者通常会迅速发生完全自主神经功能衰竭。不太严重的AAN形式经常发生，但目前尚未得到承认。为了证明AAN是一种抗体介导的神经元突触传递障碍，我们已经开发了一个强大的动物模型，实验性自身免疫性自主神经病变（EAAN），通过诱导对神经节乙酰胆碱受体的自身免疫兔。该动物模型在两个月内可预测地发展，并再现了人类疾病的表型。EAAN是第一个抗体介导的神经元突触传递障碍的疾病相关慢性模型。本项目的目的是检验EAAN开始作为一个可逆的自主神经节病变，随后逐渐的，选择性的损失节后自主神经元的假设。 具体目的是：1）定义EAAN的时间病理生理学特征，2）识别可能对人类诊断有用的EAAN生理学特征，3）通过动物模型中的对照治疗试验评价基于假设的治疗策略。该项目的第一部分是EAAN的详细生理和药理学特征与组织学变化相关，因为它们随着时间的推移而演变。将使用定量瞳孔测量和血压和心率遥测记录来评价自主神经功能并明确自主神经功能缺损。交感神经节和副交感神经节的组织学研究将包括免疫组织化学和电子显微镜，以确定神经节突触的结构。我们的目标是一个准确的定义，这种疾病的病理生理演变和相关的生理与组织病理学。这些转化研究将提供对疾病机制的深入了解，识别特征以改善临床诊断，并为新的治疗策略提供理论依据。在该项目的最后一年，将在EAAN兔中进行对照治疗试验，这在患者中是不切实际的。 除了其临床意义外，该项目还与了解神经节突触传递，神经自身免疫，获得性自主神经功能障碍的病理生理学，神经节传递的恢复和适应能力以及神经元对自身免疫攻击的脆弱性有关。

DESCRIPTION (provided by applicant): Patients with autoimmune autonomic neuropathy (AAN) classically have rapid onset of complete autonomic failure. Less severe forms of AAN occur frequently but are currently under recognized. To prove that AAN is an antibody-mediated disorder of neuronal synaptic transmission, we have developed a robust animal model, experimental autoimmune autonomic neuropathy (EAAN), by inducing autoimmunity against the neuronal ganglionic acetylcholine receptor in rabbits. The animal model develops predictably within two months and recapitulates the phenotype of the human disease. EAAN is the first disease-relevant chronic model of an antibody-mediated disorder of neuronal synaptic transmission. The objective of this project is to test the hypothesis that EAAN begins as a reversible autonomic ganglionopathy followed by a gradual, selective loss of postganglionic autonomic neurons. The specific aims are to 1) define the temporal pathophysiological profile of EAAN, 2) identify physiological features of EAAN that could be useful diagnostically in humans, and 3) evaluate hypothesis based treatment strategies through controlled treatment trials in the animal model. The first part of the project is a detailed physiological and pharmacological characterization of EAAN correlated with histological changes as they evolve over time. Quantitative pupillometry and telemetry recording of blood pressure and heart rate will be used to evaluate autonomic function and to pharmacologically dissect autonomic deficits. Histological studies of sympathetic and parasympathetic ganglia will include immunohistochemistry and electron microscopy to define the structure of the ganglionic synapse. The goal is an accurate definition of the pathophysiological evolution of this disorder and a correlation of physiology with histopathology. These translational studies will provide insight into disease mechanisms, identify characteristic features to improve clinical diagnosis, and provide rationale for new treatment strategies. In the final year of the project, controlled therapeutic trials that would be impractical in patients will be performed in EAAN rabbits. In additional to its clinical significance, this project is relevant to understanding ganglionic synaptic transmission, neurological autoimmunity, pathophysiology of acquired dysautonomia, the recuperative and adaptive capabilities of ganglionic transmission and the vulnerability of neurons to autoimmune attack.