RANTES and Eotaxin: New players in PD progression

描述(申请人提供)：帕金森氏病(PD)是第二种最常见和衰弱的与年龄相关的人类神经退行性疾病。临床上，帕金森病的特点是震颤、运动缓慢、僵硬和姿势不稳定。病理上表现为胶质细胞活化和黑质纹状体多巴胺能神经元进行性变性，与胞浆内包涵体(路易体)的存在有关。该应用程序解决了PD的一个重要方面。虽然疾病进展的速度因患者而异，但帕金森病是一种进行性神经退行性疾病。然而，人们对疾病进展背后的机制知之甚少。我们推测RANTES和嗜酸性粒细胞趋化因子可能是推动疾病进展的关键，靶向这两种趋化因子可能是控制T细胞渗透从而控制帕金森病疾病进展的重要策略。在这里，这一假设将通过在老鼠、猴子和人类身上进行的几项实验来验证。已知黑质纹状体病理在急性MPTP小鼠模型中不存在。在特定目标I下，我们将研究补充RANTES和嗜酸性粒细胞趋化因子是否会导致急性MPTP中毒小鼠的持续性和进展性疾病。已计划通过监测PD患者和年龄匹配的对照组血清中RANTES和嗜酸性粒细胞趋化因子的水平来确定PD患者是否存在较高水平的RANTES和Eoaxin。最后，我们致力于专门的目标III来描述如果阻断RANTES和嗜酸性粒细胞趋化蛋白的功能，马拉韦罗，CCR5的抑制剂和FDA批准的药物，是否可以阻止偏侧帕金森病猴子的疾病进展。这项研究的积极结果将建立RANTES和eoaxin作为PD的靶点，将基于CCR5的治疗(马拉韦罗)转化为PD临床，揭示PD进展的线索，并找到阻止PD进展的药物。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the second most common and debilitating age-associated human neurodegenerative disorder. Clinically, PD is characterized by tremor, slowness of movement, stiffness, and postural instability. Pathologically, it is indicated by activation of glial cells and progressive degeneration of the nigrostriatal dopaminergic neurons associated with the presence of intracytoplasmic inclusions (Lewy bodies). This application addresses an important aspect of PD. Although the rate of disease progression varies from patient to patient, PD is a progressive neurodegenerative disorder. However, the mechanism behind disease progression is poorly understood. We hypothesize that RANTES and eotaxin could hold the key for driving disease progression and that targeting these two chemokines may be an important strategy to control T cell infiltration and hence the disease progression in PD. Here this hypothesis will be tested from several experiments on mice, monkeys and humans. It is known that nigrostriatal pathology does not persist in acute MPTP mouse model. Under Specific aim I, we will investigate if supplementation of RANTES and eotaxin induces persistent and progressive disease in acute MPTP-intoxicated mice. Specific aim II has been planned to determine whether PD patients have higher levels of RANTES and eotaxin by monitoring the level of these two chemokines in serum of PD patients and age-matched controls. Finally, we have devoted the Specific aim III to delineate if blocking the functions of RANTES and eotaxin by maraviroc, an inhibitor of CCR5 and a FDA- approved drug, halt the disease progression in hemiparkinsonian monkeys. A positive outcome of this study will establish RANTES and eotaxin as targets for PD, translate CCR5-based treatment (maraviroc) to PD clinic, uncover the clue for the progression of PD, and find a drug to stop the progression of PD.