Urate-LRRK2 interactions in Parkinson's disease

尿酸盐-LRRK2在帕金森病中的相互作用

基本信息

批准号：
9978147
负责人：
MICHAEL A SCHWARZSCHILD
金额：
$ 40.38万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978147
关键词：
Address Albuterol Animal Model Antioxidants Astrocytes Attenuated Behavior Biological Markers Caffeine Cell model Clinical Coculture Techniques Corpus striatum structure Dependence Development Disease Disease model Drug Targeting Environmental Exposure Environmental Risk Factor Epidemiology Equilibrium Foundations Fumarates Functional disorder Genes Genetic Government Human Idiopathic Parkinson Disease Induced Mutation Inflammatory Inherited Inosine Investigation Investments Knock-out LRRK2 gene Laboratories Laboratory Study Lead Light Link Mediating Mediator of activation protein Modeling Modification Molecular Multiple Sclerosis Mus Mutation Nerve Degeneration Neurobiology Neurodegenerative Disorders Neurons Onset of illness Other Genetics Outcome Parkinson Disease Pathogenicity Pathway interactions Patients Penetrance Pesticides Pharmacologic Substance Phenotype Phosphotransferases Play Positioning Attribute Process Property Reproducibility Risk Risk Factors Role Safety Serum Signal Transduction Testing Therapeutic Toxic effect Transgenes Transgenic Organisms Urate Urate Oxidase brain cell clinical development clinical practice clinically relevant cohort cost effectiveness demographics disorder risk dopaminergic neuron drug testing efficacy trial epidemiologic data epidemiology study experimental study high risk in vivo Model insight mouse LRRK2 protein mutant neurotoxicity nuclear factor-erythroid 2 overexpression personalized medicine protective effect purine metabolism response therapeutic development urinary

项目摘要

Urate-LRRK2 interactions in Parkinson’s disease Project Summary/Abstract: Although mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common known genetic cause of Parkinson’s disease (PD), their incomplete penetrance indicates that other genetic and environmental factors play important protective roles in LRRK2 PD. Classical epidemiology studies of PD have identified molecular factors that may contribute to or protect against the underlying neurodegenerative process. Among the latter, urate an endogenous antioxidant as well as the end product of purine metabolism has emerged as a major inverse (reduced) risk factor not only for PD onset but also for its clinical progression. A convergence of these epidemiological data with laboratory evidence of its neuroprotective properties suggests that urate may be a mediator as well as a marker of favorable outcomes in idiopathic PD. New biomarker findings of lower urate levels among LRRK2 PD patients compared to people with LRRK2 mutations who have not developed PD raise the possibility that higher levels of endogenous urate contribute to the incomplete penetrance of LRRK2 mutations. The hypothesis is strengthened by evidence that urate protects dopaminergic neurons by activating the Nrf2 antioxidant response pathway, which has recently been implicated in LRRK2 pathophysiology. The current project will determine the neuroprotective potential and molecular mechanisms of urate in laboratory models and human biomarker studies of LRRK2 PD. Through its specific aims (SAs) it will characterize the neuroprotective effects of urate and their astrocyte dependence in cellular and animal models of neurodegeneration in a LRRK2+ PD (SA 1). The role of Nrf2 in the neuroprotective actions of urate and another Nrf2 activator, dimethyl fumarate (a pharmaceutical, approved for disease modification in multiple sclerosis) will be incisively addressed through a complementary set Nrf2 knockout and Nrf2 transgene rescue studies in LRRK2+ PD models (SA 2). Lastly, the interaction between urate and LRRK2 kinase activity (gauged by levels of auto-phosphorylated LRRK2) will be explored in clinical cohorts of idiopathic and LRRK2 PD (SA 3). The mechanistic and clinical insights generated by these studies may validate Nrf2 activation as a promising therapeutic strategy in LRRK2 PD, and may thereby facilitate early steps toward personalized medicine for PD. The results may also help address a growing concern over cost-effectiveness in the field of personalized medicine because Nrf2 activators are already available for clinical use. And of those poised for efficacy trials in LRRK2 PD the urate precursor inosine has been developed as a non-proprietary therapeutic with foundation and government investment. Thus the project offers realistic prospects for advancing our understanding of PD neurobiology and treatment.

帕金森氏病中的Urate-LRK2相互作用项目摘要/摘要：尽管编码富含亮氨酸的重复激酶2（LRRK2）的基因突变是最常见的帕金森氏病（PD）的已知遗传原因，它们的不完整的外渗表明其他遗传和环境因素在LRRK2 PD中起着重要的保护作用。古典流行病学 PD的研究已经确定了可能有助于或防止基础的分子因素神经退行性过程。在后者中，内源性抗氧化剂和末端嘌呤代谢的产物已成为主要的逆（减少）风险因素，不仅是PD 发作，也出于其临床进展。这些流行病学数据与实验室的融合其神经保护特性的证据表明尿酸盐可能是介体和标记物特发性PD中有利的结果。 LRRK2 PD中尿酸含量较低的新生物标志物发现与尚未开发PD的LRRK2突变的患者相比较高水平的内源性尿酸盐会导致LRRK2突变的不完全渗透率。尿酸脉通过激活尿酸保护多巴胺能神经元的证据来加强该假设 NRF2抗氧化反应途径最近与LRRK2病理生理学有关。这当前项目将确定尿酸尿酸盐的神经保护势和分子机制 LRRK2 PD的实验室模型和人类生物标志物研究。通过其特定目标（SAS）表征尿酸盐及其在细胞和动物中星形胶质细胞依赖的神经保护作用 LRRK2+ PD中的神经变性模型（SA 1）。 NRF2在神经保护作用中的作用尿酸二甲酯二甲基二甲基二甲基（一种疾病批准的药物）多发性硬化症的修饰）将通过完整的集合NRF2敏锐地解决 LRRK2+ PD模型中的敲除和NRF2转基因救援研究（SA 2）。最后，互动在尿酸和LRRK2激酶活性之间（由自磷酸化LRRK2计算）在特发性和LRRK2 PD的临床人群中探索（SA 3）。机械和临床见解这些研究产生的可能验证NRF2激活作为LRRK2中有前途的治疗策略 PD，因此可能会喜欢PD个性化医学的早期步骤。结果也可能有助于解决对个性化医学领域成本效益的日益关注，因为 NRF2激活剂已经可供临床使用。在LRRK2 PD中有效试验的那些中毒尿酸盐前体肌苷已被开发为一种非专有疗法，具有基础和政府投资。该项目为促进我们的理解提供了现实的前景 PD神经生物学和治疗。