Project 1: Identification of Early Life molecular determinants of Alzheimer's Disease pathogenesis
Project 1: Identification of Early Life molecular determinants of Alzheimer's Disease pathogenesis
批准号:
10494775
负责人:
Stacey J Rizzo
金额:
$22.44万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-01 至 2027-08-31
关键词:
AdolescenceAdolescentAdultAgeAge of OnsetAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease patientAlzheimer&aposs disease riskAlzheimer’s disease biomarkerAmyloid beta-ProteinAnatomyBehavioralBiological MarkersBiological ModelsBiopsyBirthBrainCallithrixCallithrix jacchus jacchusCellsCerebrovascular CirculationClinicalClinical DataCognitiveCommunitiesDataDiseaseDisease ProgressionDisease modelEarly Onset Alzheimer DiseaseEarly identificationEmotionalEvaluationEventFibroblastsFoundationsFutureGenerationsGeneticGenetic EngineeringGenetic RiskGoalsHumanImpaired cognitionInfantInterventionInvestigationKnowledgeKnowledge PortalLifeLiquid substanceLongevityLongitudinal StudiesMagnetic Resonance ImagingModelingMolecularMolecular ProfilingMotorMutationNeuroanatomyNeuronsOnset of illnessOutcomePathogenesisPathogenicityPatientsPhasePhenotypePhysiologicalPositron-Emission TomographyPreventionPrimatesProcessProteomeResearchResourcesSamplingSkinStagingStudy modelsSystemTissuesValidationVariantWorkagedanalytical methodcase controlcytokinedesigndifferential expressiondisease diagnosiseffective therapyhealthy aginginfancymultimodalitymultiple omicsmutantneurodevelopmentneuroinflammationneuropathologynovelpotential biomarkerpre-clinicalpresenilin-1preventrelating to nervous systemrisk variantsocialtargeted treatmenttau Proteinstau-1transcriptometranslational approach
中文摘要
项目概要 项目 1
该提案的总体目标是确定推动启动和实施的最初级联事件。
阿尔茨海默病(AD)的进展。迫切需要预防和治疗AD。我们假设
AD 的遗传风险赋予生命早期的疾病发病机制,这可以通过研究分子和
青春期之前的细胞事件将有助于预防。通过采用模型系统
更忠实地概括遗传、分子、细胞、生理、解剖和结构组织
通过灵长类动物大脑的研究,我们将能够识别 AD 的潜在驱动因素并更好地建立疾病发病机制模型
和进展以预防疾病。为了支持这些目标,该项目(项目 1)旨在确定
阿尔茨海默病发生和进展的早期生命灵长类特异性分子决定因素
狨猴经过基因工程改造,带有早老素 1 (PSEN1) 风险变异,这是一种早发性 AD 突变。的
PSEN1 狨猴模型能够评估分子、细胞和
系统层面从出生到婴儿期、青春期和老年期。该项目的具体目标是: 1)
评估 PSEN1 突变狨猴相对于健康年龄匹配和正常年龄的疾病轨迹
使用已建立的和新兴的 AD 生物标志物进行控制; 2)进行综合行为
通过纵向多模态表征 PSEN1 狨猴模型相对于健康对照的特征
从神经发育到整个生命周期的表型特征; 3)研究分子
来自成纤维细胞的神经元细胞的特征作为大脑的替代物。通过这些具体目标,我们
期望能够全面表征第一个 AD 基因工程狨猴模型
概括了在 AD 患者中观察到的 AD 相关表型的范围,包括行为、认知、
使用转化方法的生物标志物和神经病理学标志;识别早期分子变化
在坦率的 AD 神经病理学出现之前,使用多组学方法在细胞水平上进行研究
认知能力下降;并为基因工程狨猴的实用性奠定了知识基础
将 AD 风险变体作为经过验证的模型。
英文摘要
PROJECT SUMMARY PROJECT 1
The overarching aims of this proposal are to identify the initial cascade of events that drive the inception and
progression of Alzheimer’s Disease (AD). There is an urgent need to prevent, and treat AD. We hypothesize
that genetic risk for AD confers disease pathogenesis in early life that will be detected by studying molecular and
cellular events before the age of adolescence which will inform prevention. By employing a model system that
more faithfully recapitulates the genetic, molecular, cellular, physiological, anatomical and structural organization
of the primate brain, we will be able to identify underlying drivers of AD and better model disease pathogenesis
and progression in order to prevent disease. In support of these goals, this project (Project 1) aims to identify
the early life primate-specific molecular determinants of Alzheimer’s disease emergence and progression using
marmosets genetically engineered with the presenilin 1 (PSEN1) risk variant, an early onset AD mutation. The
PSEN1 marmoset models provide the ability to evaluate divergent changes at the molecular, cellular, and
systems level from birth through infancy, adolescence, and aging. The Specific Aims of this project are: 1) to
evaluate the disease trajectory of PSEN1 mutant marmosets relative to healthy age-matched and normal aged
controls using established and emerging AD biomarkers; 2) to conduct comprehensive behavioral
characterization of the PSEN1 marmoset models relative to healthy controls via longitudinal multimodal
phenotypic characterization from neurodevelopment through lifespan; and 3) investigate the molecular
signatures of neuronal cells derived from fibroblasts as a surrogate to brain. Through these specific aims, we
expect to have comprehensively characterized the first genetically engineered marmoset models of AD that
recapitulates the spectrum of AD-related phenotypes observed in AD patients for behavioral, cognitive,
biomarker, and neuropathological hallmarks using translational approaches; identified early molecular changes
at the cellular level using multi-omics approaches prior to the emergence of frank AD neuropathology and
cognitive decline; and created the foundation of knowledge for the utility of genetically engineered marmosets
with AD risk variants as validated models.
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会议论文
Role of Lifespan Intervention on the Regulation and Progression of Alzheimer's Disease
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批准号:10376882
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项目类别:
-
资助金额:$99.03万
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财政年份:2020
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负责人:Stacey J Rizzo
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依托单位:
Role of Lifespan Intervention on the Regulation and Progression of Alzheimer's Disease
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批准号:10599253
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项目类别:
-
资助金额:$82.8万
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财政年份:2020
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负责人:Stacey J Rizzo
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依托单位:
Improving Preclinical Translation in Alzheimer's Disease Research
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批准号:10469024
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项目类别:
-
资助金额:$4.94万
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财政年份:2018
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负责人:Stacey J Rizzo
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依托单位:
Improving Preclinical Translation in Alzheimer's Disease Research
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批准号:10597112
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项目类别:
-
资助金额:$4.94万
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财政年份:2018
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负责人:Stacey J Rizzo
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依托单位:
Behavioral Phenotyping
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批准号:9151760
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项目类别:
-
资助金额:$39.28万
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财政年份:2016
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负责人:Stacey J Rizzo
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依托单位:
海外基金