RANTES and Eotaxin: New players in PD progression

帕金森病（PD）是第二常见的和使人衰弱的与年龄相关的人类神经退行性疾病 disorder.临床上，PD的特征在于震颤、运动缓慢、僵硬和姿势不稳定。 病理学上，它是由神经胶质细胞的激活和黑质纹状体多巴胺能神经元的进行性变性所指示的。 与胞质内包涵体（路易体）的存在相关的神经元。该应用程序解决了 PD的重要方面。虽然疾病进展的速率因患者而异，但PD是一种进行性疾病， 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和嗜酸性粒细胞趋化因子可能是推动疾病进展的关键， 趋化因子可能是控制T细胞浸润的重要策略，从而控制PD的疾病进展。这里 这一假设将通过对小鼠、猴子和人类的几项实验进行检验。已知黑质纹状体 病理学在急性MPTP小鼠模型中不持续。在具体目标I下，我们将研究补充剂是否 RANTES和嗜酸细胞活化趋化因子诱导急性MPTP中毒小鼠的持续性和进行性疾病。具体目标二 已计划通过监测PD患者的RANTES和嗜酸性粒细胞趋化因子水平来确定PD患者是否具有较高水平的RANTES和嗜酸性粒细胞趋化因子。 这两种趋化因子在PD患者和年龄匹配的对照血清中的表达。最后，我们专门介绍了具体目标 III描述马拉韦罗是否阻断RANTES和嗜酸性粒细胞趋化因子的功能，马拉韦罗是一种CCR5抑制剂， 批准的药物，停止偏侧帕金森病猴的疾病进展。这项研究的积极成果将 建立RANTES和eotaxin作为PD的靶点，将基于CCR5的治疗（马拉韦罗）转化为PD临床， PD进展的线索，并找到阻止PD进展的药物。

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.