A slowly progressive, endogenous synucleinopathy model of Parkinson's disease

帕金森病的缓慢进展的内源性突触核蛋白病模型

• 批准号: 9211455
• 负责人: J Timothy Greenamyre
• 金额: $ 23.23万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9211455
• 关键词: Animal Model; Animals; Behavior; Behavioral; Cell physiology; Cells; Chronic; Clinical; Clinical Medicine; Data; Development; Diagnosis; Disease; Disease model; Environmental Exposure; Event; Exhibits; Exposure to; Face; Gait; Genetic; Goals; Home environment; Human; Impairment; Individual; Inflammation; Lead; Link; Mitochondria; Modeling; Mus; Nerve Degeneration; Neurologic; Normalcy; Occupational; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathology; Pesticides; Predictive Value; Rattus; Rotenone; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Time; Toxin; alpha synuclein; base; clinical development; clinically relevant; dopaminergic neuron; effective therapy; experimental study; human disease; inflammatory marker; knock-down; novel; posture instability; predictive modeling; synucleinopathy

Project Summary: Development and testing of disease-modifying therapies for Parkinson's disease (PD) is limited, in part, by lack of predictive animal models. We propose to develop and characterize a better, more predictive model, with (i) a more realistic time course, (ii) appropriate pathological and behavioral endpoints and (iii) opportunities to intervene therapeutically at clinically relevant points in the disease course (e.g., after development of symptoms). We believe the new model will set a higher and more realistic hurdle for experimental, disease-modifying therapies, and in so doing, will have more predictive value for clinical development. In brief, wildtype rats are treated with rotenone for 5 days (instead of the typical 14-21 days), during which they displayed mild parkinsonian behavior. After cessation of the rotenone, the rats recover and are behaviorally normal. After a latency of 9 – 10 weeks, all of the rats begin to exhibit mild parkinsonian signs that have continued to worsen progressively over succeeding weeks and months. Preliminary pathological assessment reveals that nigral dopamine neurons progressively accumulate abnormal endogenous α-synuclein long before behavioral signs appear and this is associated with increasing microglial activation. We now propose to further characterize this model and to test a therapeutic intervention with the following aims: (1) To characterize selected `clinical' or behavioral aspects of this model over the course of 1 year. Behaviors include the Postural Instability Test (PIT), rearing, righting behavior and gait. (2) To characterize over time the pathology in this model, including nigrostriatal cell and terminal loss, α-synuclein pathology and markers of inflammation. (3) To test a therapeutic intervention (α-synuclein knockdown) after the onset of symptoms – a situation closely analogous to clinical medicine, where a diagnosis of PD currently depends on the presence of symptoms.

项目摘要： 帕金森氏病（PD）的疾病改良疗法的开发和测试部分有限 由于缺乏预测性动物模型。我们建议发展和表征更好，更具预测性的 模型，（i）更现实的时间过程，（ii）适当的病理和行为终点以及 （iii）在疾病病程中临床相关点热干预的机会（例如， 症状发展后）。我们认为新模型将树立更高，更现实的障碍 对于实验性，修改疾病的疗法，并且这样做将具有更大的预测价值 临床发展。简而言之，野生型大鼠用鱼藤酮处理5天（而不是典型 14-21天），在此期间，他们表现出温和的帕金森氏症行为。停止烤面包酮后， 大鼠恢复并在行为上是正常的。在9至10周的潜伏期之后，所有老鼠开始开始 展示温和的帕金森氏症标志，这些标志在随后的几周内继续逐渐恶化 和几个月。初步病理评估表明，ni虫多巴胺神经元逐渐 在行为迹象出现之前，积累异常的内源性内源性α-突触核蛋白，这是 与增加小胶质激活有关。我们现在建议进一步表征此模型，并 测试具有以下目的的治疗干预措施：（1）表征选定的“临床”或 在1年的过程中，该模型的行为方面。行为包括姿势不稳定 测试（坑），饲养，矫正行为和步态。 （2）要随着时间的流逝表征该模型中的病理， 包括黑质细胞和末端损失，α-突触核蛋白病理和炎症标志物。 （3） 在症状发作后测试治疗干预措施（α-突触核蛋白敲低） - 情况 与临床医学非常相似，在该医学中，PD的诊断目前取决于存在 症状。