Characterization and targeting of a novel pathway promoting Parkinson’s Disease
促进帕金森病的新途径的表征和靶向
基本信息
- 批准号:10855706
- 负责人:
- 金额:$ 64.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-15 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAlteplaseAnimal ModelAxonBehaviorBehavioralBilateralBindingBlocking AntibodiesBrain StemCellsCentral Nervous SystemCerebral cortexCognitionCorpus striatum structureDataDementiaDementia with Lewy BodiesDevelopmentDiagnosisDiseaseDisease ProgressionDopamineDorsalEndothelial CellsEvaluationEventExhibitsImpaired cognitionImpairmentInjectionsKnock-in MouseLewy BodiesLoxP-flanked alleleLymphocyteMediatingMemantineMicrogliaModelingMovementMusN-Methyl-D-Aspartate ReceptorsNerve DegenerationNeurologicNeuronsParkinson DiseaseParkinson&aposs DementiaPathologicPathway interactionsPatientsPeptide HydrolasesPlasminogen Activator InteractionPositron-Emission TomographyProcessProteinsRadialRestRoleSignal TransductionSiteSourceSubstantia nigra structureSynapsesT cell infiltrationT-LymphocyteTestingTherapeuticTherapeutic InterventionTimeTremorWild Type Mouseadaptive immune responseage related neurodegenerationalpha synucleinarmbehavioral outcomeblood-brain barrier disruptioncytotoxicdopaminergic neuronexcitotoxicityexecutive functionexperimental studyfunctional disabilityglial activationmisfolded proteinmotor impairmentmotor symptommouse modelneuroinflammationneuron lossneurotoxicitynovelobject recognitionoverexpressionpars compactapleiotropismpre-formed fibrilpreventprotein aggregationrecruitresponsesynucleinopathyvesicular monoamine transporter
项目摘要
PROJECT SUMMARY/ABSTRACT
It is well established that many age-related neurodegenerative diseases are driven by the aggregation of
improperly processed or misfolded proteins. For example, the aggregation of α-synuclein (α-Syn) within Lewy
bodies results in a constellation of diseases referred to as synucleinopathies. These include Parkinson’s Disease
(PD) and Parkinson’s Disease Dementia (PDD). The mechanisms leading to neuronal loss in PD and PDD
remain unknown, however, neuroinflammation is thought to be a common feature, including microglial activation
in the early stages of neurodegeneration, and evidence from both animal models and patient studies supports
the involvement of the adaptive immune response and α-Syn reactive T cells. In this application we identify a
previously unrecognized pathway promoting α-Syn-induced neuroinflammation and neurodegeneration. We
show that this pathway is mediated by the protease, tissue plasminogen activator (tPA) through an interaction
with the N-methyl-D-aspartate receptor-1 (NMDAR1). Using an AAV-α-Syn mouse model we find that tPA levels
in the SN are significantly increased in mice overexpressing α-Syn, and that tPA deficiency protects
dopaminergic neurons from degeneration and reverses behavioral deficits induced by α-Syn neurotoxicity. The
action of tPA is independent of its proteolytic activity but can be prevented by treatment with Glunomab, a
blocking antibody that binds the NMDAR1 and selectively inhibits its interaction with tPA. Both tPA deficiency
and Glunomab treatment prevent neurodegeneration, normalize behavior, reduce microglia activation, and
inhibit T-cell infiltration. Based on these preliminary data we will test the hypothesis that in response to neuronal
overexpression or aggregation of α-Syn increased expression of tPA promotes neuroinflammation through
interaction with the NMDAR1 and recruitment of cytotoxic lymphocytes resulting in neurodegeneration and
leading to PD and PDD. We will test this hypothesis in two different synucleinopathy models, an AAV-α-Syn
mouse model of PD, and an α-syn preformed fibril (α-syn PFF) model of PDD in mice.
项目总结/文摘
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Daniel A Lawrence其他文献
Plasminogen promotes sarcoma growth and suppresses the accumulation of tumor-infiltrating macrophages
纤溶酶原促进肉瘤生长并抑制肿瘤浸润巨噬细胞的积累
- DOI:
10.1038/sj.onc.1205951 - 发表时间:
2002-12-16 - 期刊:
- 影响因子:7.300
- 作者:
Alejandro Curino;David J Mitola;Hannah Aaronson;Grainne A McMahon;Kamran Raja;Achsah D Keegan;Daniel A Lawrence;Thomas H Bugge - 通讯作者:
Thomas H Bugge
Daniel A Lawrence的其他文献
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{{ truncateString('Daniel A Lawrence', 18)}}的其他基金
A Novel PAI-1 Function Drives Lung Fibrosis
PAI-1 的新功能可驱动肺纤维化
- 批准号:
10605479 - 财政年份:2022
- 资助金额:
$ 64.71万 - 项目类别:
The Role of PAI-1 in Cerebral Microvascular Dysfunction and the Development of Alzheimer’s Disease Neuropathology
PAI-1 在脑微血管功能障碍和阿尔茨海默病发展中的作用 神经病理学
- 批准号:
10314556 - 财政年份:2021
- 资助金额:
$ 64.71万 - 项目类别:
The Role of PAI-1 in Cerebral Microvascular Dysfunction and the Development of Alzheimer’s Disease Neuropathology
PAI-1 在脑微血管功能障碍和阿尔茨海默病发展中的作用 神经病理学
- 批准号:
10629303 - 财政年份:2021
- 资助金额:
$ 64.71万 - 项目类别:
Mechanism of thrombolytic tPA induced intracerebral hemorrhage after stroke
溶栓tPA致脑卒中后脑出血的机制
- 批准号:
8655918 - 财政年份:2012
- 资助金额:
$ 64.71万 - 项目类别:
Mechanism of thrombolytic tPA induced intracerebral hemorrhage after stroke
溶栓tPA致脑卒中后脑出血的机制
- 批准号:
8487469 - 财政年份:2012
- 资助金额:
$ 64.71万 - 项目类别:
Mechanism of thrombolytic tPA induced intracerebral hemorrhage after stroke
溶栓tPA致脑卒中后脑出血的机制
- 批准号:
8345099 - 财政年份:2012
- 资助金额:
$ 64.71万 - 项目类别:
Characterization of the role of PAI-1 in lipid metabolism
PAI-1 在脂质代谢中的作用表征
- 批准号:
8247042 - 财政年份:2011
- 资助金额:
$ 64.71万 - 项目类别:
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