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.

尿酸盐-LRRK2在帕金森病中的相互作用项目摘要/摘要：尽管编码富含亮氨酸重复激酶 2 (LRRK2) 的基因突变是最常见的帕金森病 (PD) 的已知遗传原因，其不完全外显率表明其他遗传和环境因素在 LRRK2 PD 的经典流行病学中发挥重要的保护作用。帕金森病的研究已经确定了可能有助于或预防潜在帕金森病的分子因素。在后者中，尿酸是一种内源性抗氧化剂，也是最终的神经退行性过程。嘌呤代谢产物已成为主要的反向（减少）危险因素，不仅是帕金森病的主要反向（减少）危险因素发病率以及其临床进展。这些流行病学数据与实验室数据的融合。其神经保护特性的证据表明尿酸盐可能是一种介质和标记物 LRRK2 PD 中尿酸盐水平较低的新生物标志物发现与未患 PD 的 LRRK2 突变患者相比，这种可能性增加较高水平的内源性尿酸导致 LRRK2 突变的不完全外显。有证据表明尿酸盐通过激活多巴胺能神经元来保护多巴胺能神经元，这一假设得到了加强。 Nrf2 抗氧化反应途径，最近与 LRRK2 病理生理学有关。当前的项目将确定尿酸盐的神经保护潜力和分子机制 LRRK2 PD 的实验室模型和人类生物标志物研究将通过其特定目标 (SA) 进行。表征尿酸盐的神经保护作用及其在细胞和动物中的星形胶质细胞依赖性 LRRK2+ PD 神经变性模型 (SA 1) Nrf2 在神经保护作用中的作用。尿酸盐和另一种 Nrf2 激活剂富马酸二甲酯（一种药物，已批准用于治疗疾病）多发性硬化症的修饰）将通过补充集 Nrf2 得到彻底解决 LRRK2+ PD 模型中的敲除和 Nrf2 转基因拯救研究 (SA 2)。尿酸盐和 LRRK2 激酶活性（通过自磷酸化 LRRK2 的水平来衡量）之间的关系将在特发性和 LRRK2 PD 的临床队列中进行了探索（SA 3）。这些研究产生的结果可能会验证 Nrf2 激活作为 LRRK2 的一种有前途的治疗策略 PD，从而可能促进针对 PD 的个性化医疗的早期步骤。帮助解决个性化医疗领域对成本效益日益增长的担忧，因为 Nrf2 激活剂已可供临床使用，其中一些已准备好进行 LRRK2 PD 疗效试验。尿酸盐前体肌苷已被开发为一种非专有治疗药物，具有基础和因此，该项目为增进我们的理解提供了现实的前景。 PD 神经生物学和治疗。