RANTES and Eotaxin: New players in PD progression

描述（由申请人提供）：帕金森病（PD）是第二种最常见和使人衰弱的年龄相关性人类神经退行性疾病。临床上，PD的特征是震颤、运动缓慢、僵硬和姿势不稳定。在病理学上，其表现为神经胶质细胞的活化和黑质纹状体多巴胺能神经元的进行性变性，与胞质内包涵体（路易体）的存在相关。本申请解决了PD的一个重要方面。虽然疾病进展的速率因患者而异，但PD是一种进行性神经退行性疾病。然而，疾病进展背后的机制知之甚少。我们假设RANTES和eotaxin可能是驱动疾病进展的关键，靶向这两种趋化因子可能是控制T细胞浸润的重要策略，因此PD的疾病进展。在这里，我们将通过对小鼠、猴子和人类的几项实验来验证这一假设。已知黑质纹状体病理学在急性MPTP小鼠模型中不持续存在。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在急性MPTP中毒小鼠中诱导持续性和进行性疾病。具体目标II已计划通过监测PD患者和年龄匹配对照血清中这两种趋化因子的水平来确定PD患者是否具有较高水平的RANTES和嗜酸性粒细胞趋化因子。最后，我们致力于特定目标III，以描述通过马拉韦罗（一种CCR 5抑制剂和FDA批准的药物）阻断RANTES和嗜酸性粒细胞趋化因子的功能是否阻止偏侧帕金森病猴的疾病进展。该研究的积极结果将确立RANTES和eotaxin作为PD的靶点，将基于CCR 5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.