Uric Acid:novel therapeutic target for Parkinson's Disease

性状（由申请方提供）：在人体中，尿酸是一种强抗氧化剂，也是嘌呤代谢的终产物。低血尿酸现在成为原发性帕金森病（PD）的主要分子危险因素。此外，我们的初步研究结果表明，早期PD的血浆和CSF尿酸水平是两项大型前瞻性临床研究中基于临床和神经影像学测量的PD进展速度较慢的高度显著预测因素。这些观察结果支持了一种新的神经保护作用的尿酸或其决定因素在PD，并促使我们探索他们的作用在PD的动物模型。该提议所追求的核心假设是，尿酸及其决定因素在PD动物模型中赋予对多巴胺能神经元变性的保护作用。我们将研究尿酸及其前体肌苷在PD小鼠MPTP模型中的神经保护作用，使用互补的遗传和药理学方法来升高尿酸（全身或局部;急性或慢性）。拟议的工作将定义一个原型之间的相互作用的环境神经毒物和新确定的候选神经保护剂，这可能是特别适合治疗干预。拟议的实验将为为什么尿酸预测降低风险和减缓疾病进展建立生物学基础。该项目的机制见解可能会证实预防和减缓PD的新颖而现实的药理学策略。 公共卫生相关性该研究旨在阐明尿酸及其前体肌苷在PD原型毒物模型中的神经保护作用。因此，这些研究的结果可能为尿酸和PD之间的反向流行病学和临床关联建立生物学基础，并为未来的机制研究提供基础。总之，本提案的具体目标旨在为PD和相关神经系统疾病的病理生理学、流行病学和潜在治疗提供概念上重要且临床相关的见解。

DESCRIPTION (provided by applicant): In humans uric acid constitutes a strong antioxidant as well as the end product of purine metabolism. Lower blood uric acid is now emerging as a major molecular risk factor for idiopathic Parkinson's disease (PD). Moreover, our preliminary findings have demonstrated that plasma and CSF uric acid levels in early PD are highly significant predictors of a slower rate of PD progression based on clinical and neuroimaging measures in two large prospective clinical studies. These observations support a novel neuroprotective effect of uric acid or its determinants in PD, and prompted us to explore their role in an animal model of PD. The core hypothesis pursued by this proposal is that uric acid and its determinants confer protection against dopaminergic neuron degeneration in an animal model of PD. We will investigate the neuroprotective effects of uric acid and its precursor inosine in the mouse MPTP model of PD, using complementary genetic and pharmacological approaches to elevating uric acid (systemically or locally; acutely or chronically). The proposed work will define a prototypical interaction between an environmental neurotoxicant and a newly identified candidate neuroprotectant, which may be particularly amenable to therapeutic interventions. The proposed experiments stand to establish a biological basis for why uric acid predicts reduced risk and slower progression of the disease. Mechanistic insights from the project may substantiate novel yet realistic pharmacological strategies for preventing and slowing PD. PUBLIC HEALTH RELEVANCE The proposed research stands to elucidate neuroprotective effects of uric acid and its precursor inosine in a prototypic toxicant model of PD. The results of these studies may thus establish a biological basis for the inverse epidemiological and clinical associations between uric acid and PD, and provide a foundation for future mechanistic investigations. Together, the specific aims of this proposal seek to provide conceptually important and clinically relevant insights into the pathophysiology, the epidemiology and potentially the treatment of PD and related neurological disorders.