HEART DYSAUTONOMIA IN PARKINSON'S DISEASE

帕金森病的心脏自主神经功能障碍

• 批准号: 8358232
• 负责人: MARINA EMBORG
• 金额: $ 0.78万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358232
• 关键词: Adult; Affect; Age; Animal Model; Area; Arrhythmia; Autonomic Dysfunction; Autonomic nervous system; Basal Ganglia; Biological Assay; Blood; Blood Pressure Monitors; Cardiac; Catecholamines; Chemicals; Clinic; Development; Dopamine; Dysautonomias; Electrocardiogram; Epinephrine; Functional disorder; Funding; Grant; Heart; Hypotension; Image; Macaca mulatta; Methods; Modeling; Monitor; Monkeys; Movement Disorders; National Center for Research Resources; Nerve Degeneration; Nervous system structure; Neurons; Neurotoxins; Organ; Oxidopamine; Parkinson Disease; Patients; Positron-Emission Tomography; Preparation; Primates; Principal Investigator; Publications; Replacement Therapy; Research; Research Infrastructure; Resources; Services; Source; Symptoms; Testing; Troponin; Ultrasonography; United States National Institutes of Health; Wisconsin; analog; cost; in vivo; intravenous administration; male; meta-hydroxyephedrine; nerve supply; nonhuman primate; research clinical testing; uptake

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Objective: To develop tests to access autonomic dysfunction induced by systemic administration of the neurotoxin 6 hydroxydopamine. PD is associated with loss of autonomic innervation. The heart is one key organ affected. As such, PD patients present heart dysautonomia symptoms like ortostatic hypotension or arrhythmias. Currently, there are not well characterized nonhuman primate models of these problems. Through an interdisciplinary team consisting of PD experts, cardiologists and imaging experts, we are developing a battery of tests to access autonomic dysfunction induced by systemic administration of the neurotoxin 6-hydroxydopamine. Preliminary results from this project suggest that intravenous administration of 6-OHDA induces neurodegeneration of catecholaminergic neurons innervating the heart and can be used to model heart autonomic dysfunction in PD. Progress: Parkinson's disease (PD) is a movement disorder affecting the basal ganglia, yet neurodegeneration also occurs in other areas of the nervous system resulting in dysautonomia, or dysfunction of the autonomic nervous system. Traditional dopamine (DA) replacement therapies for PD patients currently do not provide the relief from them and development of new treatments is difficult due to the lack of animal models. In this study we aimed to develop a cardiac dysautonomia model in rhesus monkeys and generate a toolbox of methods that can be utilized in clinic to assess neurodegeneration in the heart. We hypothesized that the administration of 6-hydroxydopamine 6-OHDA would induce cardiac dysfunction in the monkeys through neurodegeneration of the ganglionic catecholaminergic neurons innervating the heart. Two adult male rhesus monkeys (ages 5-7 yrs old, 7-9kg) were evaluated before and after intravenous administration of 6-OHDA through clinical evaluations, EKG, ultrasound, blood pressure monitoring, troponin and catecholamine blood chemical assays. In addition, in vivo monitoring of neurodegeneration of catecholaminergic terminals in the heart was achieved with positron emission tomography (PET) using the nor-epinephrine analog 11C-meta-Hydroxyephedrine (MHED). Baseline PET scans of the two normal monkeys displayed normal MHED uptake in the heart wall. PET images obtained 7 days post 6-OHDA revealed an extensive decrease in MHED uptake, which confirms loss of catecholaminergic terminals. These preliminary results suggest that intravenous administration of 6-OHDA induces neurodegeneration of catecholaminergic neurons innervating the heart and can be used to model heart autonomic dysfunction in PD. This research uses WNPRC Assay Services and CPI. A publication is in preparation.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 目的：开发测试以访问由全身性施用神经毒素6羟基多巴胺引起的自主功能障碍。 PD与自主神经神经的丧失有关。心脏是受影响的一个关键器官。作为 这样的PD患者表现出心脏动作障碍症状，例如环形低血压或 心律不齐。当前，这些特征的非人类灵长类动物模型没有很好的特征 问题。通过由PD专家，心脏病专家和 成像专家，我们正在开发一系列测试以访问自主功能障碍 由全身给药神经毒素6-羟基多巴胺诱导。 该项目的初步结果表明，静脉注射6-OHDA 诱导心脏支配的儿茶酚胺能神经元的神经变性，可以是 用于在PD中对心脏自主神经功能障碍进行建模。 进展：帕金森氏病（PD）是一种影响基底神经节的运动障碍，但神经退行性也发生在神经系统的其他区域，导致功能障碍或自主神经系统功能障碍。当前的PD患者的传统多巴胺（DA）替代疗法无法减轻他们的缓解，由于缺乏动物模型，很难开发新疗法。在这项研究中，我们旨在在恒河猴中开发心脏动作障碍模型，并生成一个可以在诊所中使用的方法箱来评估心脏中的神经变性。我们假设给予6-羟基多巴胺6-OHDA会通过神经节感染性儿童能神经元的神经变性诱导猴子的心脏功能障碍。通过临床评估静脉注射6-OHDA之前和之后，评估了两只成年男性恒河猴（5-7岁，7-9kg），EKG，超声，血压监测，肌钙蛋白和儿茶酚胺血液化学化学分析。此外，使用非肾上腺素类似物11c-meta-meta--羟基蛋白酶（MHED），通过正电子发射断层扫描（PET）实现了心脏中儿茶酚胺能末端神经退行性的体内监测。两只普通猴子的基线PET扫描在心脏壁上显示出正常的MHED摄取。 6-OHDA后7天获得的PET图像显示，MHED摄取量大大降低，这证实了儿茶酚胺能末端的损失。 这些初步结果表明，静脉注射6-OHDA诱导神经心脏的儿茶酚胺能神经元的神经退行性，可用于模拟PD中心脏自主神经功能障碍。 该研究使用WNPRC测定服务和CPI。 正在准备出版物。