权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10640903
负责人：
MICHAEL A SCHWARZSCHILD
金额：
$ 38.55万
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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640903
关键词：
Acceleration 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 Link Mediating Mediator 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 Persons 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 neuroprotection 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.

帕金森病中的尿酸-LRRK 2相互作用项目概要/摘要：虽然编码富含亮氨酸重复序列激酶2（LRRK 2）的基因突变是最常见的，帕金森氏病（PD）的已知遗传原因，他们的不完全遗传表明，遗传和环境因素在LRRK 2 PD中起重要的保护作用。经典流行病学 PD的研究已经确定了可能有助于或保护免受潜在疾病的分子因素。神经退化过程在后者中，尿酸盐是一种内源性抗氧化剂，嘌呤代谢产物已成为PD的主要反向（降低）风险因素，发病，但也为临床进展。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以及标记物，在特发性PD中的有利结果。LRRK 2 PD中尿酸盐水平较低的新生物标志物发现与未发生PD的LRRK 2突变患者相比，高水平的内源性尿酸盐导致LRRK 2突变的不完全转移。尿酸盐通过激活多巴胺能神经元保护多巴胺能神经元的证据加强了这一假设。 Nrf 2抗氧化反应途径，最近已被牵连在LRRK 2的病理生理学。的目前的项目将确定尿酸盐的神经保护潜力和分子机制， LRRK 2 PD的实验室模型和人类生物标志物研究。通过其具体目标，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 LRRK 2 + PD中的神经变性模型（SA 1）。Nrf 2在神经保护作用中的作用尿酸盐和另一种Nrf 2激活剂，富马酸二甲酯（一种药物，批准用于疾病在多发性硬化症的修改）将通过一个互补集Nrf 2 在LRRK 2 + PD模型中的敲除和Nrf 2转基因拯救研究（SA 2）。最后，互动尿酸盐和LRRK 2激酶活性之间的关系（通过自磷酸化LRRK 2的水平来衡量）将是在特发性和LRRK 2 PD的临床队列中进行了研究（SA 3）。机械和临床的见解这些研究产生的结果可能会验证Nrf 2激活作为LRRK 2中有前途的治疗策略 PD，并因此可能促进早期步骤向个性化药物PD。结果还可能有助于解决个性化医疗领域日益增长的成本效益问题， nrf 2激活剂已经可用于临床。在那些准备进行LRRK 2 PD疗效试验的患者中，尿酸盐前体肌苷已经被开发为一种非专有的治疗剂，政府投资因此，该项目提供了现实的前景，以促进我们的理解， PD神经生物学和治疗。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Short-term lipopolysaccharide treatment leads to astrocyte activation in LRRK2 G2019S knock-in mice without loss of dopaminergic neurons.

短期脂多糖治疗导致 LRRK2 G2019S 敲入小鼠中的星形胶质细胞活化，且多巴胺能神经元不丢失。

DOI：
10.21203/rs.3.rs-4076333/v1
发表时间：
2024
期刊：
Research square
影响因子：
0
作者：
Ngo,HoangKieuChi;Le,Hoang;Ayer,SamuelJ;Crotty,GraceF;Schwarzschild,MichaelA;Bakshi,Rachit
通讯作者：
Bakshi,Rachit

The PSG 32nd Annual Symposium on Etiology, Pathogenesis, and Treatment of Parkinson Disease and Other Movement Disorders.

PSG 第 32 届帕金森病和其他运动障碍的病因、发病机制和治疗年度研讨会。

DOI：
10.1002/mds.29002
发表时间：
2022
期刊：
Movement disorders : official journal of the Movement Disorder Society
影响因子：
0
作者：
通讯作者：

Planning for Prevention of Parkinson Disease: Now Is the Time.

DOI：
10.1212/wnl.0000000000200789
发表时间：
2022-08-16
期刊：
Neurology
影响因子：
9.9
作者：
通讯作者：

What to Test in Parkinson Disease Prevention Trials? Repurposed, Low-Risk, and Gene-Targeted Drugs.

DOI：
10.1212/wnl.0000000000200238
发表时间：
2022-08-16
期刊：
Neurology
影响因子：
9.9
作者：
通讯作者：

The STEPWISE study: study protocol for a smartphone-based exercise solution for people with Parkinson's Disease (randomized controlled trial).

DOI：
10.1186/s12883-023-03355-8
发表时间：
2023-09-12
期刊：
BMC NEUROLOGY
影响因子：
2.6
作者：
Schootemeijer, Sabine;de Vries, Nienke M.;Macklin, Eric A.;Roes, Kit C. B.;Joosten, Hilde;Omberg, Larsson;Ascherio, Alberto;Schwarzschild, Michael A.;Bloem, Bastiaan R.
通讯作者：
Bloem, Bastiaan R.