Experimental Dysautonomia: Pathogenesis and Treatment

实验性自主神经功能障碍：发病机制和治疗

• 批准号: 6988709
• 负责人: STEVEN A VERNINO
• 金额: $ 17.53万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6988709
• 关键词: acetylcholine; autoimmune disorder; autonomic disorder; autonomic ganglion; autonomic nervous system; cell mediated cytotoxicity; electrocardiography; electron microscopy; high performance liquid chromatography; immunocytochemistry; immunopathology; laboratory rabbit; nervous system disorder diagnosis; nervous system disorder therapy; neural degeneration; neural transmission; neurons; nicotinic receptors; nonhuman therapy evaluation; parasympathetic nervous system; pathologic process; pupillography; serology /serodiagnosis; synapses; telemetry

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.

描述（由申请人提供）：自身免疫性神经病（AAN）经典的患者迅速发作完全自主衰竭。 AAN的严重形式较少，但目前已被认可。为了证明AAN是一种神经元突触传播的抗体介导的疾病，我们通过诱导自身免疫来诱导自身免疫，以针对Rabbits中的神经元神经节乙酰胆碱受体诱导自身免疫性，从而开发了一种健壮的动物模型，实验性自主神经神经病（EAAN）。动物模型可以在两个月内发展，并概括了人类疾病的表型。 EAAN是抗体介导的神经元突触传播疾病的第一个与疾病的慢性模型。该项目的目的是检验EAAN以可逆的自主神经节病开始的假设，然后逐渐选择性地丧失了后神经自主神经元。 具体目的是1）定义EAAN的时间病理生理特征，2）确定EAAN的生理特征，可以在人类中诊断为有用，3）通过动物模型中的对照治疗试验评估基于假设的治疗策略。该项目的第一部分是EAAN的详细生理和药理表征与组织学变化随着时间的流逝而相关。血压和心率的定量化学计量学和遥测记录将用于评估自主神经功能和药理剖析自主缺陷。交感神经和副交感神经的组织学研究将包括免疫组织化学和电子显微镜，以定义神经节突触的结构。目标是对这种疾病的病理生理演化的准确定义，以及生理学与组织病理学的相关性。这些翻译研究将提供有关疾病机制的洞察力，确定特征以改善临床诊断，并为新的治疗策略提供理由。在该项目的最后一年，将在Eaan兔子中进行对照治疗试验，这将是不切实际的。 除临床意义外，该项目与理解神经节突触传播，神经系统自身免疫性，获得性动力学障碍的病理生理学，神经节传播的恢复性和适应性能力以及神经元对自身免疫攻击的脆弱性。