RANTES and Eotaxin: New players in PD progression

描述（由申请人提供）：帕金森病（PD）是第二常见和衰弱的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。病理表现为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，与胞浆内包涵体（路易小体）的存在有关。这个应用程序解决了PD的一个重要方面。虽然疾病进展率因患者而异，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尚不清楚。我们假设RANTES和eotaxin可能是驱动PD疾病进展的关键，靶向这两种趋化因子可能是控制T细胞浸润从而控制PD疾病进展的重要策略。在这里，这一假设将在老鼠、猴子和人类身上进行几项实验。已知在急性MPTP小鼠模型中黑质纹状体病理不持续。在Specific aim I下，我们将研究在急性mptp中毒小鼠中，补充RANTES和eotaxin是否会诱导持续和进行性疾病。特定目的II计划通过监测PD患者和年龄匹配对照者血清中RANTES和eotaxin两种趋化因子的水平来确定PD患者是否有更高水平的RANTES和eotaxin。最后，我们专门研究了特异性目的III，以确定是否阻断RANTES和eotaxin的功能，由maraviroc（一种CCR5抑制剂和FDA批准的药物）阻断半帕金森猴子的疾病进展。本研究的积极成果将确立RANTES和eotaxin作为PD的靶点，将基于ccr5的治疗（maraviroc）转化为PD临床，揭示PD进展的线索，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.