Experimental Dysautonomia: Pathogenesis and Treatment

描述(由申请人提供)：典型的自身免疫性自主神经病变(AAN)患者很快就会出现完全的自主神经衰竭。不太严重的AAN经常发生，但目前还没有被认识到。为了证明AAN是一种抗体介导的神经元突触传递障碍，我们建立了一种强大的动物模型-实验性自身免疫性自主神经病变(EAAN)，方法是诱导兔抗神经节型乙酰胆碱受体的自身免疫。动物模型在两个月内可预见地发展，并概括了人类疾病的表型。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。本项目的目的是验证这样一种假设，即Eaan开始时是一种可逆的自主神经节病，随后是节后自主神经细胞的逐渐、选择性丧失。 其具体目的是：1)确定EAAN的时间病理生理学特征；2)确定可用于人类诊断的EAAN的生理特征；3)通过动物模型的对照治疗试验，评估基于假说的治疗策略。该项目的第一部分是EAAN随着时间的推移与组织学变化相关的详细的生理和药理学特征。血压和心率的定量斜率测量和遥测记录将用于评估自主神经功能和从药理上解剖自主神经缺陷。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。目标是准确定义这种疾病的病理生理学演变，并将生理学与组织病理学联系起来。这些转化研究将提供对疾病机制的洞察，识别改善临床诊断的特征，并为新的治疗策略提供理论基础。在该项目的最后一年，将在伊安兔身上进行对患者不切实际的对照治疗试验。 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、神经节传递的康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.