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
基本信息
- 批准号:10581664
- 负责人:
- 金额:$ 23.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAffinityAlzheimer&aposs DiseaseAmyloid beta-ProteinAnimal ModelAutopsyAutoradiographyBindingBiological AssayBiological MarkersClinicalClinical ResearchCompetitive BindingCytoplasmCytoplasmic InclusionDataDepositionDevelopmentDiagnosisDiseaseDisease ProgressionFluorescenceFrontotemporal DementiaGeneticGrowthHigh PrevalenceImaging ligandsIn VitroIndividualLewy BodiesLewy neuritesLibrariesLigandsMeasurementMeasuresMethodsMolecular DiagnosisMonitorMultiple System AtrophyNeurodegenerative DisordersNeuronsParkinson DiseasePathologicPathologyPositron-Emission TomographyPreparationProgressive Supranuclear PalsyPropertyProtein BiosynthesisProteinsRadiolabeledStainsStructureTherapeuticTissue StainsTissuesTracerTritiumWorkabeta accumulationaccurate diagnosisalpha synucleinbiomarker developmentbrain tissueclinical diagnosiscorticobasal degenerationdensitydiagnostic accuracydisease mechanisms studyexperimental studyimaging agentimprovedin vivomonomernovelnovel strategiespersonalized approachpreventprotein aggregationradioligandradiotracerscreeningtargeted biomarkertau Proteinstau aggregationtherapeutic developmenttherapeutic targettherapy development
项目摘要
Abstract
Multiple System Atrophy (MSA) is a neurodegenerative disorder defined by the accumulation of alpha-
synuclein (Asyn) fibrils in glial cytoplasmic inclusions (GCIs). The accumulation of Asyn fibrils is a feature
shared with Parkinson disease, where Asyn fibrils accumulate in neuronal cytoplasmic and neuritic inclusions
known as Lewy bodies and Lewy neurites. Evidence from genetic, autopsy and disease mechanism studies
support Asyn fibrils as a therapeutic target. It is also a target for biomarker development. 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 MSA, and provide a biomarker for disease progression. In this application we propose to screen
and identify novel leads for developing an Asyn imaging agent for MSA. 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 screen natively fluorescent compounds for
binding Asyn fibrils in vitro followed by assessment of whether compounds bind to Asyn-containing GCIs in
postmortem MSA brain tissue sections. A final step is to determine whether compounds selectively bind to
GCIs but do not bind to other types of pathologic fibril accumulation in postmortem brain tissue sections.
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
多系统萎缩(MSA)是一种神经退行性疾病,其定义为α-淀粉样蛋白的积累,
神经胶质细胞质内含物(GCI)中的突触核蛋白(Asyn)纤维。Asyn纤维的积累是一个特征
与帕金森病共享,其中Asyn纤维积聚在神经元细胞质和神经炎包涵体中
叫做路易体和路易神经突来自遗传学、尸检和疾病机制研究的证据
支持脱辅基原纤维作为治疗靶点。它也是生物标志物开发的目标。首要任务是
开发一种PET成像剂,可以量化Asyn在活体中的沉积,作为生物标志物,
临床研究中的目标参与。Asyn PET显像剂还可以提高诊断的准确性。
诊断MSA,并提供疾病进展的生物标志物。在本申请中,我们建议筛选
并鉴定用于开发用于MSA的Asyn显像剂的新先导物。我们开发了一种新的筛选方法
一种鉴定可作为开发Asyn成像的先导化合物的新化合物的方法
剂这种新方法使用荧光测量来筛选天然荧光化合物,
在体外结合Asyn原纤维,然后评估化合物是否结合到含有Asyn的GCI中。
死后MSA脑组织切片最后一步是确定化合物是否选择性地结合到
GCI,但不结合其他类型的病理性纤维积累在死后的脑组织切片。
发现具有所需性质的化合物将用氚放射性标记,以进一步
使用放射性配体结合测定和放射自显影来表征它们的结合特性。化合物
在该项目中确定的,可以用作进一步研究的线索,以开发Asyn成像剂。结果
该项目还将进一步优化这种新的筛选方法,以确定具有
成像剂所需的结合性质。
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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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:
$ 23.63万 - 项目类别:
IDENTIFICATION OF FLUORESCENT LIGANDS FOR ALPHA SYNUCLEIN FIBRILS
α 突触核蛋白原纤维荧光配体的鉴定
- 批准号:
9789973 - 财政年份:2018
- 资助金额:
$ 23.63万 - 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:
$ 23.63万 - 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:
$ 23.63万 - 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:
$ 23.63万 - 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:
$ 23.63万 - 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:
$ 23.63万 - 项目类别:
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