Project 3: LRRK2 mediated macrophage responses in PD
项目 3:LRRK2 介导的 PD 巨噬细胞反应
基本信息
- 批准号:10469390
- 负责人:
- 金额:$ 38.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-30 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AlabamaAnimal ModelAntisense OligonucleotidesAttenuatedAutomobile DrivingAutopsyBasic ScienceBiochemical PathwayBioinformaticsBloodBone MarrowBone Marrow TransplantationBrainBrain DiseasesBrain regionCell membraneCell physiologyCellsClinicalCytokine ReceptorsDerivation procedureDisease modelDisease susceptibilityGTP BindingGenesGeneticGenetic VariationHLA-DR AntigensHeritabilityImmuneImmunohistochemistryInflammationInflammatoryInflammatory ResponseInterferonsKnock-outKnockout MiceLRRK2 geneLaboratoriesLeukocytesLinkMeasuresMediatingMediationMicrogliaMidbrain structureModelingMosaicismMutationNatural ImmunityNerve DegenerationNeuronsOntologyParkinson DiseasePathogenesisPathogenicityPathway interactionsPatientsPeripheralPharmacologyPhosphotransferasesProductionProteinsRNA InterferenceRattusRodentSerumSubstantia nigra structureSurfaceSystemTechniquesTherapeuticTransgenic MiceTransgenic OrganismsTransplantationUp-RegulationVesicleWorkadaptive immunityalpha synucleinbone cellchemokine receptorcohortcytokinedisorder controlgenetic variantimmune activationimmune functioninduced pluripotent stem cellkinase inhibitormacrophagemolecular sequence databasemonocytemutation carrierneuroinflammationneuroprotectionnovelpars compactapredictive modelingreceptorrecruitresponsesmall moleculesynucleintooltraffickingtranscriptomics
项目摘要
Project 3- Summary “LRRK2 mediated macrophage responses in PD”
Post-mortem studies show that brains susceptible to Parkinson disease (PD) develop α-
synuclein inclusions in vulnerable neurons together with immune cell activation. Peripheral immune
cells are recruited to the most vulnerable brain regions such as the substantia nigra pars compacta.
Historically the interpretation of immune cell activation in the PD brain and pathogenesis has been
difficult to understand. However, recent genetic and transcriptomic profiling studies using new
sequence databases and gene ontology compendia show that immune cell function may underlie
much of the heritable aspects of PD susceptibility. These recent studies highlight a gene known as
leucine-rich repeat kinase 2 in driving some of the connection between immune function and PD
susceptibility. Rare genetic variants in LRRK2 are among the most common known genetic causes of
PD. In the P20 Exploratory center, we found that LRRK2 protein is highly expressed in peripheral
macrophages that are recruited nearby neurons in the brain that harbor α-synuclein inclusions.
Studies with global LRRK2-transgenic and knockout mice and rats suggest that LRRK2 may control
damaging pro-inflammatory responses in the brain through function in these macrophages.
As part of the proposed Alabama Udall Center to study “Innate and Adaptive Immunity in
Parkinson Disease,” we will define peripheral macrophage responses driven by LRRK2 in α-synuclein
induced neurodegeneration. Using genetic, pharmacological, and transplantation approaches, we will
restrict LRRK2 activation and inhibition to the periphery and in bone-marrow derived immune cells in
rat models of α-synuclein induced neurodegeneration. In parallel, we will study LRRK2 function in
macrophages isolated from patient blood to determine whether LRRK2 mutations exacerbate pro-
inflammatory responses in PD susceptibility. Further, we will examine whether macrophage
responses from de novo PD patients with elevated LRRK2 expression show elevated pro-
inflammatory responses and whether these can be rescued with LRRK2 kinase inhibitors and RNAi
approaches. With this work, we hope to gain a better understanding of LRRK2 function in
macrophages in neurodegeneration and proof-of-principle therapeutic approaches that might be
explored for neuroprotection in LRRK2-linked PD.
项目3-总结“LRRK2介导的帕金森病巨噬细胞反应”
尸检研究表明,易患帕金森病(PD)的大脑会发展成α-
脆弱神经元中的突触核蛋白包涵体与免疫细胞激活。外周免疫
细胞被招募到最脆弱的大脑区域,如黑质致密部。
历史上对帕金森病脑内免疫细胞激活和发病机制的解释一直是
很难理解。然而,最近的遗传和转录图谱研究使用新的
序列数据库和基因本体论纲要表明,免疫细胞功能可能是
帕金森病易感性的许多可遗传方面。这些最近的研究突出了一种被称为
富含亮氨酸的重复蛋白激酶2驱动免疫功能与帕金森病之间的一些联系
敏感度。LRRK2中罕见的遗传变异是最常见的已知遗传原因之一
警察。在P20探索中心,我们发现LRRK2蛋白在外周高表达
巨噬细胞被招募到大脑中含有α-突触核蛋白包涵体的神经元附近。
对全球LRRK2转基因和基因敲除小鼠和大鼠的研究表明,LRRK2可能控制
通过这些巨噬细胞的功能破坏大脑中的促炎反应。
作为拟议的阿拉巴马州尤德尔中心的一部分,该中心将研究
帕金森病,我们将在α-突触核蛋白中定义LRRK2驱动的外周巨噬细胞反应
诱发神经退行性变。使用遗传学、药理学和移植方法,我们将
将LRRK2的激活和抑制限制在外周和骨髓来源的免疫细胞中
α-突触核蛋白诱导的大鼠神经变性模型。同时,我们将研究LRRK2函数
从患者血液中分离巨噬细胞以确定LRRK2突变是否加剧了
帕金森病易感性中的炎症反应。此外,我们将检查巨噬细胞是否
LRRK2表达升高的新发PD患者的反应显示PRO-2升高
炎症反应以及LRRK2激酶抑制剂和RNAi能否挽救这些反应
接近了。通过这项工作,我们希望能更好地理解LRRK2在
巨噬细胞在神经退行性变中的作用和可能的原则性治疗方法
探讨LRRK2连锁PD的神经保护作用。
项目成果
期刊论文数量(0)
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Andrew B West的其他文献
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{{ truncateString('Andrew B West', 18)}}的其他基金
Project 3: LRRK2 mediated macrophage responses in PD
项目 3:LRRK2 介导的 PD 巨噬细胞反应
- 批准号:
9976625 - 财政年份:2018
- 资助金额:
$ 38.71万 - 项目类别:
Exosome LRRK2 in Predicting Parkinson Disease Phenotypes
外泌体 LRRK2 预测帕金森病表型
- 批准号:
9135110 - 财政年份:2016
- 资助金额:
$ 38.71万 - 项目类别:
Exosome LRRK2 in Predicting Parkinson Disease Phenotypes
外泌体 LRRK2 预测帕金森病表型
- 批准号:
9282760 - 财政年份:2016
- 资助金额:
$ 38.71万 - 项目类别:
LRRK2 and Other Novel Exosome Proteins in Parkinson's Disease
LRRK2 和其他新型外泌体蛋白在帕金森病中的作用
- 批准号:
9035559 - 财政年份:2015
- 资助金额:
$ 38.71万 - 项目类别:
LRRK2 and Other Novel Exosome Proteins in Parkinson's Disease
LRRK2 和其他新型外泌体蛋白在帕金森病中的作用
- 批准号:
8554393 - 财政年份:2012
- 资助金额:
$ 38.71万 - 项目类别:
LRRK2 and Other Novel Exosome Proteins in Parkinson's Disease
LRRK2 和其他新型外泌体蛋白在帕金森病中的作用
- 批准号:
8472329 - 财政年份:2012
- 资助金额:
$ 38.71万 - 项目类别:
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