Sigma-1 Receptor Radioligand for Translational Research in Alzheimer's Disease
用于阿尔茨海默病转化研究的 Sigma-1 受体放射性配体
基本信息
- 批准号:10670485
- 负责人:
- 金额:$ 83.29万
- 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:2022-09-15 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AgeAgonistAlzheimer&aposs DiseaseAlzheimer&aposs disease diagnosisAlzheimer&aposs disease modelAlzheimer&aposs disease patientAlzheimer&aposs disease riskAlzheimer&aposs disease therapeuticAlzheimer&aposs disease therapyAmyloid beta-ProteinAmyotrophic Lateral SclerosisAnimal Disease ModelsAnimal DiseasesApplications GrantsAutoradiographyBindingBiochemicalBioenergeticsBiological MarkersBrainCalciumCalcium SignalingCellsCessation of lifeCholesterol HomeostasisClinicalClinical TrialsComplexCoupledDataDegenerative DisorderDementiaDevelopmentDiagnosisDiagnosticDiseaseDisease ProgressionDoseDrug KineticsDrug TargetingEarly DiagnosisEndoplasmic ReticulumEquilibriumEtiologyEvaluationFunctional disorderGenerationsGenetic PolymorphismHumanHuntington DiseaseITPR1 geneImageImmune responseImmunoglobulin binding proteinsInositolInvestigationKineticsLabelLigandsLinkMeasurementMediatingMembraneMental DepressionMental disordersMethodsMitochondriaMolecularMolecular ChaperonesMonitorMonkeysMorphologyNerve DegenerationNeurofibrillary TanglesNeuronsOralOrganOxidative StressParkinson DiseasePathogenesisPathologicPathologyPersonsPharmacologyPlayPositron-Emission TomographyProceduresProductionProteinsProtocols documentationReactionReceptor GeneRegulationReproducibilityResearchRisk FactorsRoleSafetyScanningSchizophreniaSignal TransductionSkeletonSliceSpecificitySurrogate MarkersSynapsesSynaptic VesiclesTestingToxic effectTranslational ResearchTranslationsTreatment outcomeWorkapolipoprotein E-4calcium metabolismcholinergiccognitive functiondensitydisease mechanisms studydonepezildosimetrydrug candidateearly detection biomarkersenantiomerexperienceexperimental studyfirst-in-humanglucose-regulated proteinshealthy volunteerhuman studyhuman subjecthyperphosphorylated tauimaging agentin vivoinsightlipid metabolismmild cognitive impairmentmitochondrial dysfunctionmouse modelnervous system disorderneuropsychiatric disordernonhuman primatenovelpre-clinicalradiochemicalradioligandreceptorrelating to nervous systemsigma-1 receptortau Proteinstherapeutic developmenttherapeutic targettoolwhole body imaging
项目摘要
In this grant application we propose to develop and validate an optimal 18F-labeled sigma-1 (σ1) receptor
radioligand for translational research in Alzheimer’s disease (AD) to further elucidate the role of σ1 receptor in
AD pathogenesis and progression, to probe longitudinal changes in σ1 receptor in AD animal models, along with
the synapse biomarker synaptic vesicle protein 2A (SV2A), and AD pathologic biomarkers b-amyloid (Ab) and
tau, and to explore the potential of σ1 receptor imaging for early diagnosis of AD.
AD is a progressive degenerative disorder that afflicts 6 million people in the USA. From a diagnostic
perspective, AD is increasingly viewed along a continuum from preclinical AD, to mild cognitive impairment (MCI),
and to AD-dementia. The clinical dementia of AD is coupled to a distinct pathology, with plaques composed of
b-amyloid (Ab), neurofibrillary tangles of hyperphosphorylated tau protein, and synaptic loss. However, the
molecular mechanism(s) of AD pathogenesis is complex and remains elusive. Several hypotheses have been
put forward, including the b-amyloid hypothesis, the misfolded tau protein hypothesis, the cholinergic hypothesis,
and the involvement of oxidative stress and calcium dyshomeostasis. Before the accumulation of plaques and
tangles, the biochemical and morphological changes, such as altered calcium, cholesterol, and lipid metabolism,
altered mitochondrial dynamics, and reduced bioenergetic interaction, are all closely associated with functions
localized to the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs). The σ1 receptor is
situated at the MAM. The most recent research has located the earliest Ab generation in AD to neurons in the
MAM, and its critical regulation by the σ1 receptor, thereby confirming the central role of σ1 receptor in AD
pathogenesis. As such the σ1 receptor is considered an important target for AD therapeutic development. As a
surrogate marker for mitochondria function and regulator of Ab production on the MAM, it also holds great
promise as a biomarker for diagnosis of AD at its earliest stage.
The research proposed in this application will bridge an important gap in the understanding of the σ1 receptor
in AD pathogenesis and progression by leveraging the unique expertise and experience at Yale in novel PET
radioligand development, AD mechanism study, and therapeutic target identification. Investigation of the σ1
receptor in AD animal models longitudinally in relation to biomarkers for synaptic density, Ab, and tau, is a natural
extension of our ongoing research. When carried to completion, this project will provide further insights into the
etiology of AD, and help identify a most sensitive and effective biomarker for early AD diagnosis, and for
monitoring of disease progression and the efficacy of emerging AD therapies.
在这项资助申请中,我们提出开发和验证最佳的18F标记的σ-1(σ1)受体
用于阿尔茨海默病(AD)转化研究的放射性配体,以进一步阐明σ1受体在阿尔茨海默病中的作用。
AD发病机制和进展,以探索AD动物模型中σ1受体的纵向变化,沿着
突触生物标志物突触囊泡蛋白2A(SV 2A)和AD病理生物标志物β-淀粉样蛋白(Ab),
目的探讨σ1受体显像在AD早期诊断中的应用价值。
AD是一种进行性退行性疾病,在美国困扰着600万人。从诊断
从这个角度来看,AD越来越被沿着从临床前AD到轻度认知障碍(MCI)的连续体来看待,
和AD痴呆症AD的临床痴呆与独特的病理学相关联,斑块由以下组成:
b-淀粉样蛋白(Ab)、过度磷酸化tau蛋白的神经元缠结和突触丢失。但
AD发病机制的分子机制是复杂的,并且仍然是难以捉摸的。有几个假设
提出的,包括b-淀粉样蛋白假说,错误折叠的tau蛋白假说,胆碱能假说,
以及氧化应激和钙稳态异常的参与。在斑块积聚之前,
缠结、生物化学和形态学变化,如钙、胆固醇和脂质代谢的改变,
线粒体动力学的改变和生物能量相互作用的减少都与功能密切相关。
定位于内质网(ER)膜(MAMs)。σ1受体是
位于MAM。最新的研究已经将AD中最早的Ab产生定位于下丘脑中的神经元。
MAM及其受σ1受体的关键调节,从而证实σ1受体在AD中的中心作用
发病机制因此,σ1受体被认为是AD治疗开发的重要靶标。作为
作为线粒体功能的替代标记物和MAM上Ab产生的调节剂,它也具有很大的
有望作为AD早期诊断的生物标志物。
这项申请中提出的研究将弥合对σ1受体理解的重要空白
利用耶鲁大学在新型PET方面的独特专业知识和经验,
放射性配体开发、AD机制研究和治疗靶点鉴定。σ1的研究
AD动物模型中的受体与突触密度生物标志物Ab和tau纵向相关,是一种天然的
我们正在进行的研究的延伸。完成后,该项目将进一步深入了解
AD的病因学,并帮助确定最敏感和有效的生物标志物,用于早期AD诊断,
监测疾病进展和新兴AD疗法的疗效。
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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YIYUN HENRY HUANG其他文献
YIYUN HENRY HUANG的其他文献
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{{ truncateString('YIYUN HENRY HUANG', 18)}}的其他基金
Sigma-1 Receptor Radioligand for Translational Research in Alzheimer's Disease
用于阿尔茨海默病转化研究的 Sigma-1 受体放射性配体
- 批准号:
10586550 - 财政年份:2023
- 资助金额:
$ 83.29万 - 项目类别:
Validation of Fluorine-18 radioligand for PET imaging of synaptic density in Alzheimer's disease
验证氟 18 放射性配体对阿尔茨海默病突触密度 PET 成像的效果
- 批准号:
10319957 - 财政年份:2020
- 资助金额:
$ 83.29万 - 项目类别:
Validation of Fluorine-18 radioligand for PET imaging of synaptic density in Alzheimer's disease
验证氟 18 放射性配体对阿尔茨海默病突触密度 PET 成像的效果
- 批准号:
10078584 - 财政年份:2020
- 资助金额:
$ 83.29万 - 项目类别:
Validation of Fluorine-18 radioligand for PET imaging of synaptic density in Alzheimer's disease
验证氟 18 放射性配体对阿尔茨海默病突触密度 PET 成像的效果
- 批准号:
10541827 - 财政年份:2020
- 资助金额:
$ 83.29万 - 项目类别:
Novel PET Radiotracer for Muscarinic M1 Receptor
用于毒蕈碱 M1 受体的新型 PET 放射性示踪剂
- 批准号:
9365677 - 财政年份:2017
- 资助金额:
$ 83.29万 - 项目类别:
Novel PET Radiotracer for Muscarinic M1 Receptor
用于毒蕈碱 M1 受体的新型 PET 放射性示踪剂
- 批准号:
10001184 - 财政年份:2017
- 资助金额:
$ 83.29万 - 项目类别:
Novel agonist tracers for PET imaging of kappa opioid receptors
用于 kappa 阿片受体 PET 成像的新型激动剂示踪剂
- 批准号:
8899631 - 财政年份:2011
- 资助金额:
$ 83.29万 - 项目类别:
Novel agonist tracers for PET imaging of kappa opioid receptors
用于 kappa 阿片受体 PET 成像的新型激动剂示踪剂
- 批准号:
8693652 - 财政年份:2011
- 资助金额:
$ 83.29万 - 项目类别:
Novel agonist tracers for PET imaging of kappa opioid receptors
用于 kappa 阿片受体 PET 成像的新型激动剂示踪剂
- 批准号:
8190570 - 财政年份:2011
- 资助金额:
$ 83.29万 - 项目类别:
Novel agonist tracers for PET imaging of kappa opioid receptors
用于 kappa 阿片受体 PET 成像的新型激动剂示踪剂
- 批准号:
8318066 - 财政年份:2011
- 资助金额:
$ 83.29万 - 项目类别:
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