RANTES and Eotaxin: New players in PD progression

帕金森氏病(PD)是人类第二常见的与年龄相关的神经退行性变 无序。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。 病理上表现为神经胶质细胞激活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(路易小体)相关的神经元。此应用程序针对的是 帕金森病的重要方面。尽管疾病进展的速度因患者而异，但帕金森病是一种进行性疾病。 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 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，并针对这两个因素 趋化因子可能是控制T细胞浸润从而控制帕金森病病情进展的重要策略。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 急性MPTP小鼠模型不存在病理改变。在具体目标一下，我们将调查是否补充 RANTES和嗜酸性粒细胞趋化因子在急性MPTP中毒小鼠中诱导持续性和进行性疾病。特定目标II 已经计划通过监测RANTES和嗜酸性粒细胞趋化素水平来确定PD患者是否有更高的RANTES和Eoaxin水平 两种趋化因子在帕金森病患者和年龄匹配的对照组血清中的表达。最后，我们致力于具体的目标 3.划定CCR5抑制剂马拉韦罗和FDA是否阻断RANTES和嗜酸性粒细胞趋化因子的功能- 批准的药物，阻止偏侧帕金森症猴子的疾病进展。这项研究的积极结果将 建立RANTES和嗜酸性粒细胞趋化因子作为PD的靶点，将基于CCR5的治疗(马拉韦罗)转化为PD临床，发现 为帕金森病的进展提供线索，并找到一种药物来阻止帕金森病的进展。

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.