Uric Acid:novel therapeutic target for Parkinson's Disease

尿酸：帕金森病的新治疗靶点

基本信息

批准号：
7862626
负责人：
MICHAEL A SCHWARZSCHILD
金额：
$ 21.06万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-15 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7862626
关键词：
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine 3-nitrotyrosine Acute Animal Model Antioxidants Attenuated Binding Biological Blood Chronic Clinical Clinical Research Corpus striatum structure Development Diet Disease Disease Progression Dopamine Epidemiology Foundations Functional disorder Future Gene Mutation Genetic Goals Human Hyperuricemia In Vitro Increased Uric Acid Level Inosine Investigation Link Measures Modeling Molecular Mus Nerve Nerve Degeneration Neuronal Injury Neuroprotective Agents Neurotoxins Oxidases Parkinson Disease Plasma Principal Investigator Purines Research Risk Risk Factors Rodent Role Substantia nigra structure Therapeutic Intervention Uric Acid Work base clinically relevant density dopamine transporter dopaminergic neuron in vivo insight intraperitoneal mouse model nervous system disorder neurochemistry neuroimaging neurotoxicity new therapeutic target novel oxidative damage prevent programs prospective public health relevance purine purine metabolism research study toxicant

项目摘要

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.

描述（由申请人提供）：在人类中，尿酸构成了嘌呤代谢的强抗氧化剂和最终产物。现在，血液尿酸现在已成为特发性帕金森氏病（PD）的主要分子危险因素。此外，我们的初步发现表明，早期PD中的血浆和CSF尿酸水平是基于两项大型前瞻性临床研究的临床和神经影像学测量的PD进展速度较慢的高度显着预测指标。这些观察结果支持尿酸或其在PD中的决定因素的新型神经保护作用，并促使我们探索它们在PD动物模型中的作用。该提议提出的核心假设是，尿酸及其决定因素允许在PD动物模型中保护对多巴胺能神经元变性。我们将使用互补的遗传和药理学方法来研究尿酸MPTP模型中尿酸及其前体内因的神经保护作用，以升高尿酸（全身或局部或局部；急性或慢性）。提出的工作将定义环境神经毒性与新确定的候选神经保护剂之间的典型相互作用，这可能特别适合治疗干预措施。拟议的实验旨在建立生物学基础，说明为什么尿酸可以预测疾病的风险降低和较慢的进展。该项目的机械洞察力可以证实预防和放缓PD的新型但现实的药理策略。公共卫生相关性该提出的研究旨在阐明尿酸及其前体肌苷在PD的原型有毒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之间的逆流行病学和临床关联建立生物学基础，并为将来的机械研究提供了基础。共同，该提案的具体目的旨在提供有关病理生理学，流行病学以及可能治疗PD和相关神经系统疾病的概念上重要和临床相关的见解。