LRRK2 and inflammasome pathway in Parkinson's disease
帕金森病中的 LRRK2 和炎症小体通路
基本信息
- 批准号:10640900
- 负责人:
- 金额:$ 64.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAnimal ModelBiologicalBiological AssayBloodBrainCell DeathCellsCerebrospinal FluidChronic DiseaseCodeCollaborationsCrohn&aposs diseaseDevelopmentDiseaseDisease ProgressionDoseEncephalitisGTP BindingGenesGeneticGuanosine Triphosphate PhosphohydrolasesHumanIL18 geneImmuneImmune System DiseasesImmunityIn VitroInduction of ApoptosisInfectionInflammasomeInflammationInflammation MediatorsInflammatoryInflammatory ResponseInjuryInterleukin-1 betaInterventionKnock-inKnock-in MouseKnock-outKnockout MiceLRRK2 geneLeprosyLinkLipopolysaccharidesMapsMediatingMediatorMicrogliaMolecularMusMutationNatural ImmunityNerve DegenerationNeurodegenerative DisordersNeurogliaNeuronal InjuryNeuronsOnset of illnessParkinson DiseasePathogenesisPathogenicityPathologyPathway interactionsPatientsPharmaceutical PreparationsPhosphotransferasesPilot ProjectsPoint MutationProductionPropertyProtein FamilyProteinsRiskRisk FactorsRoleSignal TransductionSmall Interfering RNATestingTherapeuticToxic effectTransgenic Organismsbrain tissuecytokinedesigndopaminergic neurongain of functiongenetic approachglial activationin vivoinduced pluripotent stem cellinnate immune functioninsightknock-downmutantnervous system disorderneuroinflammationnoveloverexpressionpharmacologicpotential biomarkerprotein expressionreceptorsensorsporadic Parkinson&aposs Diseasetargeted biomarkertool
项目摘要
Abstract:
The LRRK2 locus, coding for the LRRK2 (Leucine Rich Repeat Kinase 2) protein, is a major risk factor for
Parkinson’s disease (PD), and mutations in the LRRK2 gene contribute to both genetic and sporadic PD.
Intriguingly, the LRRK2 locus also confers increased risk for Crohn’s disease and leprosy, and LRRK2 is
expressed in immune cells, neurons and glia. We recently discovered that LRRK2 interacts with NOD-like
receptor (NLR) sensor family proteins (NLRPs), NLRP1 and NLRP3. NLRP proteins are key mediators of innate
immunity, and are components of inflammasomes. We propose to test the hypothesis that mutant LRRK2
interacts with and activates the NLRP3- and NLRP1-inflammasomes leading to microglial activation and
neurodegeneration contributing to PD pathology. In Aim 1, we will characterize the interaction of LRRK2 with
NLRP1 and NLRP3 in vitro and in vivo. In Aim 2, we will investigate whether mutant LRRK2 activates the NLRP3-
infammasome in microglial activation, leading to neuroinflammation and degeneration in vitro and in vivo. In
Aim3, we will examine whether mutant LRRK2 activates the NLRP1-inflammsome in neurons, resulting in
neurodegeneration. These studies will elucidate mechanisms underlying LRRK2-linked inflammasome pathway
in neurodegeneration and immune dysfunction. They may also have broader implications for other neurological
diseases related to neuroinflammation. The understanding of NLRP/LRRK2-linked pathways in PD pathogenesis
may reveal potential biomarkers, and may provide novel targets for development of disease-modifying
therapeutic strategies. Thus, this project has the potential for significant impact, and benefits those suffering from
PD and other neurodegenerative diseases.
摘要:
LRRK 2基因座编码LRRK 2(富含亮氨酸重复序列激酶2)蛋白,是糖尿病的主要风险因素。
帕金森病(PD)和LRRK 2基因突变导致遗传性和散发性PD。
有趣的是,LRRK 2基因座也赋予克罗恩病和麻风病的风险增加,并且LRRK 2是
在免疫细胞、神经元和神经胶质中表达。我们最近发现LRRK 2与NOD样蛋白相互作用,
受体(NLR)传感器家族蛋白(NLRP),NLRP 1和NLRP 3。NLRP蛋白是先天性免疫缺陷的关键介质。
免疫,并且是炎性小体的组分。我们建议测试突变LRRK 2
与NLRP 3和NLRP 1炎性体相互作用并激活,导致小胶质细胞激活,
导致PD病理学的神经变性。在目标1中,我们将表征LRRK 2与
NLRP 1和NLRP 3在体外和体内。在目标2中,我们将研究突变体LRRK 2是否激活NLRP 3 - 1。
infammasome在小胶质细胞活化中的作用,导致体外和体内的神经炎症和变性。在
目的3,我们将检查突变LRRK 2是否激活神经元中的NLRP 1-炎性小体,导致
神经变性这些研究将阐明LRRK 2相关炎性体通路的机制
神经退化和免疫功能紊乱它们也可能对其他神经系统疾病产生更广泛的影响。
与神经炎症有关的疾病。NLRP/LRRK 2相关通路在帕金森病发病机制中的作用
可能揭示潜在的生物标志物,并可能为疾病修饰的发展提供新的靶点。
治疗策略因此,该项目有可能产生重大影响,并使那些遭受
PD和其他神经退行性疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Christopher A Ross其他文献
Neurodegenerative Diseases: Dentatorubral-pallidoluysian atrophy (DRPLA): model for Huntington's disease and other polyglutamine diseases
神经退行性疾病:齿状红核苍白球萎缩症 (DRPLA):亨廷顿病和其他多聚谷氨酰胺疾病的模型
- DOI:
- 发表时间:
2005 - 期刊:
- 影响因子:0
- 作者:
Christopher A Ross;L. Ellerby;Jonathan D. Wood;Federick C. Nucifora - 通讯作者:
Federick C. Nucifora
Transcription meets metabolism in neurodegeneration
转录在神经退行性变中与代谢相遇
- DOI:
10.1038/nm1106-1239 - 发表时间:
2006-11-01 - 期刊:
- 影响因子:50.000
- 作者:
Christopher A Ross;Leslie Michels Thompson - 通讯作者:
Leslie Michels Thompson
Protein aggregation and neurodegenerative disease
蛋白质聚集与神经退行性疾病
- DOI:
10.1038/nm1066 - 发表时间:
2004-07-01 - 期刊:
- 影响因子:50.000
- 作者:
Christopher A Ross;Michelle A Poirier - 通讯作者:
Michelle A Poirier
Neuronal signaling pathways: genetic insights into the pathophysiology of major mental illness
神经元信号通路:对重大精神疾病病理生理学的遗传学见解
- DOI:
10.1038/npp.2009.137 - 发表时间:
2009-12-10 - 期刊:
- 影响因子:7.100
- 作者:
Russell L Margolis;Christopher A Ross - 通讯作者:
Christopher A Ross
Christopher A Ross的其他文献
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{{ truncateString('Christopher A Ross', 18)}}的其他基金
LRRK2 and inflammasome pathway in Parkinson's disease
帕金森病中的 LRRK2 和炎症小体通路
- 批准号:
10292714 - 财政年份:2021
- 资助金额:
$ 64.29万 - 项目类别:
LRRK2 and inflammasome pathway in Parkinson's disease
帕金森病中的 LRRK2 和炎症小体通路
- 批准号:
10432114 - 财政年份:2021
- 资助金额:
$ 64.29万 - 项目类别:
Immortalized Striatal Precursor Neurons as a Screenable Model of HD
永生化纹状体前体神经元作为 HD 的筛选模型
- 批准号:
10550333 - 财政年份:2018
- 资助金额:
$ 64.29万 - 项目类别:
Validation of Novel Pathogenic Htt Post-Translational Modifications (PTMs)
新型致病性 Htt 翻译后修饰 (PTM) 的验证
- 批准号:
9008084 - 财政年份:2014
- 资助金额:
$ 64.29万 - 项目类别:
Validation of Novel Pathogenic Htt Post-Translational Modifications (PTMs)
新型致病性 Htt 翻译后修饰 (PTM) 的验证
- 批准号:
9222822 - 财政年份:2014
- 资助金额:
$ 64.29万 - 项目类别:
Validation of Novel Pathogenic Post-Translational Modifications of Huntingtin, and of Modifying Enzymes as Therapeutic Targets for Huntington's Disease
亨廷顿蛋白的新型致病性翻译后修饰以及修饰酶作为亨廷顿病治疗靶点的验证
- 批准号:
10599877 - 财政年份:2014
- 资助金额:
$ 64.29万 - 项目类别:
Validation of Novel Pathogenic Htt Post-Translational Modifications (PTMs)
新型致病性 Htt 翻译后修饰 (PTM) 的验证
- 批准号:
8826197 - 财政年份:2014
- 资助金额:
$ 64.29万 - 项目类别:
Validation of Novel Pathogenic Htt Post-Translational Modifications (PTMs)
新型致病性 Htt 翻译后修饰 (PTM) 的验证
- 批准号:
8659881 - 财政年份:2014
- 资助金额:
$ 64.29万 - 项目类别:
Immortalized Human Strital Precursors as a Cell Model of HD
永生化人类骨骼前体作为 HD 细胞模型
- 批准号:
8533521 - 财政年份:2013
- 资助金额:
$ 64.29万 - 项目类别:
Immortalized Human Strital Precursors as a Cell Model of HD
永生化人类骨骼前体作为 HD 细胞模型
- 批准号:
8616821 - 财政年份:2013
- 资助金额:
$ 64.29万 - 项目类别:
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