IDENTIFICATION OF FLUORESCENT LIGANDS FOR ALPHA SYNUCLEIN FIBRILS
α 突触核蛋白原纤维荧光配体的鉴定
基本信息
- 批准号:9789973
- 负责人:
- 金额:$ 22.88万
- 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 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAmyloid beta-ProteinAutopsyAutoradiographyBindingBinding SitesBiological AssayBiological MarkersBrainClinical ResearchDataDepositionDevelopmentDiseaseDisease ProgressionFluorescenceGenesGrowthImaging ligandsIn VitroIndividualLeadLewy BodiesLibrariesLigand BindingLigandsMeasurementMeasuresMethodsMonitorMutationNeocortexNeuritesNeurofibrillary TanglesNeuronsParkinson DiseaseParkinson&aposs DementiaPathogenesisPathologyPharmaceutical ChemistryPositioning AttributePositron-Emission TomographyPreparationPropertyProteinsRadiolabeledRoleSeedsSenile PlaquesStainsStructureTherapeuticTissue StainsTissuesTracerTritiumabeta accumulationaccurate diagnosisalpha synucleinbasebrain tissuedensitydiagnostic accuracyexperimental studyimaging agentimprovedin vivonovelnovel strategiespreventprotein aggregateradioligandradiotracerscreeningtargeted biomarkertau Proteinstau aggregationuptake
项目摘要
Abstract
Parkinson's Disease (PD) is defined by the accumulation of alpha-synuclein (Asyn) fibrils in neuronal
cytoplasmic and neuritic inclusions known as Lewy bodies and Lewy neurites. The role of Asyn in
pathogenesis is supported by the identification of dominant mutations in the gene encoding Asyn (SNCA) in
rare familial versions of PD. PD progression, particularly the development of dementia in PD, is associated
with more widespread deposition of Asyn throughout the brain, including neocortex. Multiple therapeutic
approaches targeting Asyn accumulation are being pursued. A leading priority is to develop a PET imaging
agent that can quantify the deposition of Asyn in living individuals, as a biomarker for target engagement in
clinical studies. An Asyn PET imaging agent would also improve the accuracy of diagnosis for PD, and provide
a biomarker for disease progression. We developed a new screening approach to identify novel compounds
that can be pursued as leads for the development of an Asyn imaging agent. This new approach uses
fluorescence measurements to identify a subset of natively fluorescent compounds in a commercial library. We
then use fluorescence measurements to screen natively fluorescent compounds for binding Asyn fibrils in vitro
followed by assessment of whether compounds bind to Asyn-containing Lewy bodies in postmortem PD brain
tissue sections. A final step is to determine whether compounds selectively bind to Lewy bodies but do not bind
to amyloid plaques or neurofibrillary tangles in postmortem brain tissue sections. The project will use this
approach to screen 5000 fluorescent compounds. Compounds found to have the desired properties will be
radiolabeled with tritium in order to further characterize their binding properties using radioligand binding
assays and autoradiography. The compounds identified in the project can be used as leads in further studies to
develop an Asyn imaging agent. Results from the project will also enable further optimization of this new
screening approach to identify compounds with the binding properties needed for an imaging agent.
摘要
项目成果
期刊论文数量(0)
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PAUL T KOTZBAUER其他文献
PAUL T KOTZBAUER的其他文献
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{{ truncateString('PAUL T KOTZBAUER', 18)}}的其他基金
Imaging Ligands for Alpha-Synuclein Fibril Accumulation in Multiple System Atrophy
多系统萎缩中α-突触核蛋白原纤维积累的成像配体
- 批准号:
10452228 - 财政年份:2022
- 资助金额:
$ 22.88万 - 项目类别:
Imaging Ligands for Alpha-Synuclein Fibril Accumulation in Multiple System Atrophy
多系统萎缩中α-突触核蛋白原纤维积累的成像配体
- 批准号:
10581664 - 财政年份:2022
- 资助金额:
$ 22.88万 - 项目类别:
STRUCTURAL BIOLOGY OF ALPHA-SYNUCLEIN IN LEWY BODY DEMENTIA
路易体痴呆中α-突触核蛋白的结构生物学
- 批准号:
10246509 - 财政年份:2018
- 资助金额:
$ 22.88万 - 项目类别:
STRUCTURAL BIOLOGY OF ALPHA-SYNUCLEIN IN LEWY BODY DEMENTIA
路易体痴呆中α-突触核蛋白的结构生物学
- 批准号:
10473717 - 财政年份:2018
- 资助金额:
$ 22.88万 - 项目类别:
Structural Biology of Alpha-Synuclein in Lewy Body Dementia
路易体痴呆中α-突触核蛋白的结构生物学
- 批准号:
10729722 - 财政年份:2018
- 资助金额:
$ 22.88万 - 项目类别:
STRUCTURAL BIOLOGY OF ALPHA-SYNUCLEIN IN LEWY BODY DEMENTIA
路易体痴呆中α-突触核蛋白的结构生物学
- 批准号:
10023948 - 财政年份:2018
- 资助金额:
$ 22.88万 - 项目类别:
STRUCTURAL BIOLOGY OF ALPHA-SYNUCLEIN IN LEWY BODY DEMENTIA
路易体痴呆中α-突触核蛋白的结构生物学
- 批准号:
9791034 - 财政年份:2018
- 资助金额:
$ 22.88万 - 项目类别:
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