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.

项目概要： 帕金森病 (PD) 疾病缓解疗法的开发和测试在一定程度上是有限的， 由于缺乏预测性动物模型，我们建议开发和表征更好、更具预测性的动物模型。 模型，具有（i）更现实的时间过程，（ii）适当的病理和行为终点以及 (iii) 在病程中的临床相关点进行治疗干预的机会（例如， 症状出现后）我们相信新模型将设定更高、更现实的障碍。 对于实验性的疾病修饰疗法，这样做将具有更大的预测价值 简而言之，野生型大鼠用鱼藤酮治疗 5 天（而不是典型的治疗）。 14-21天），在此期间他们表现出轻度帕金森病行为，在停止使用鱼藤酮后， 经过 9-10 周的潜伏期后，所有大鼠都开始恢复并表现正常。 轻微表现出帕金森病症状，并在接下来的几周内逐渐恶化 初步病理评估显示黑质多巴胺神经元逐渐增多。 早在行为迹象出现之前就积累了异常的内源性α-突触核蛋白，这是 我们现在建议进一步表征该模型并与增加的小胶质细胞激活相关。 测试治疗干预措施，其目的如下：(1) 描述选定的“临床”或 该模型在一年内的行为方面包括姿势不稳定性。 测试 (PIT)、站立、扶正行为和步态 (2) 为了表征该模型随时间的病理变化， 包括黑质纹状体细胞和终末损失、α-突触核蛋白病理学和炎症标志物 (3)。 在症状出现后测试治疗干预（α-突触核蛋白敲低）——一种情况 与临床医学非常相似，目前 PD 的诊断取决于是否存在 症状。