Amyloid Beta Oligomer Induction of Alzheimer's Disease in Nonhuman Primates
淀粉样β寡聚体在非人灵长类动物中诱导阿尔茨海默氏病
基本信息
- 批准号:9765816
- 负责人:
- 金额:$ 4.9万
- 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:2018-08-20 至 2019-03-07
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAgeAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmericanAnimal ModelAnimalsAppearanceAutopsyBackBasic ScienceBiochemicalBiochemistryBiodistributionBiological MarkersBiotechnologyBrainCercopithecus pygerythrusCessation of lifeCharacteristicsClinicalClinical TrialsCognitionCognitiveConsensusDataDependenceDepositionDevelopmentDiagnosticDiffusionDiseaseDisease ProgressionDoseDrug KineticsDrug TargetingEarly DiagnosisEndocrinologyEvaluationFailureFamily CaregiverFosteringFunctional disorderFutureGene MutationGeneticGenomicsGoalsHealthcare SystemsHeart DiseasesHippocampus (Brain)HistologicHumanImmunohistochemistryImmunologyImpaired cognitionImpairmentIncidenceIndustryInfusion proceduresInjectionsInstitutesInterventionIntrathecal InjectionsLaboratoriesLeadLifeLongevityMagnetic Resonance ImagingMeasurementMeasuresMemoryMemory LossMissionModelingMonkeysMortality DeclineMusNational Institute of Allergy and Infectious DiseaseNational Institute of Biomedical Imaging and BioengineeringNational Institute of Environmental Health SciencesNational Institute of Mental HealthNational Institute of Neurological Disorders and StrokeNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNeuronsOutcome StudyPathologicPathologyPatientsPharmacodynamicsPharmacologic SubstancePharmacologyPhasePhysiologyPlayPre-Clinical ModelPreclinical TestingPrefrontal CortexPrevalenceProgram DevelopmentPublic HealthRare DiseasesRattusRegimenReproducibilityResearchResourcesRiskRisk FactorsRodentRoleSenile PlaquesStandardizationSymptomsSynapsesSystemTestingTimeTissuesTranslatingTranslationsTreatment EfficacyUnited States National Institutes of HealthWorkabeta oligomerbaseclinical diagnosticsclinical efficacycognitive abilitycognitive testingcombatcost effectivedesigndisabilityeffective therapyfamilial Alzheimer diseasegray matterhealth economicshuman modelin vivoinnovationmodel developmentmouse modelnonhuman primatenovelnovel diagnosticsnovel strategiesnovel therapeuticspreclinical studypreventsocialsuccesssymptom treatmenttau aggregationtherapeutic developmenttreatment strategy
项目摘要
PROJECT SUMMARY
Patients with Alzheimer's disease (AD) suffer a progressive loss of memory and cognitive ability, and eventual
loss of basic bodily functions and death. Currently 11% of Americans over 65 have AD and its incidence and
toll on the healthcare system continues to rise with significant societal impact. There are no treatments for AD
to prevent its inexorable course, and a principal obstacle to developing new therapies for AD has been the
inadequacy of available preclinical modeling, which almost exclusively involves rodents. As nonhuman
primates (NHPs) share greater homology to humans than rodents in all respects, including genomics and
physiology, cognitive processing, neuronal network complexity, white/gray matter ratios, dynamics of
drug/target interactions, and the triggers of age-associated pathophysiology, the long-term goal of this project
is to develop a new NHP model of AD that can be standardized and deployed in rigorous, reproducible studies
to overcome critical current deficiencies in translating preclinical studies into novel clinical diagnostic strategies
and therapies. The objective of this application is to expand and advance recent preliminary work on a new
NHP model of AD involving intrathecal administration of amyloid β-oligomers (AβOs). The hypothesis is that
AβOs will trigger a cascade of accelerated pathology that mimics the changes occurring in the brains of AD
patients. This hypothesis is based on a growing consensus in the AD research field, backed by strong data,
that AβOs are likely the toxic species that provoke deposition of the characteristic tangles and plaques in the
brain together with loss of synapses and neurons and associated cognitive decline. The hypothesis will be
tested in statistically meaningful designs by pursing the following two specific aims: 1) Determine the
appropriate dose of AβO and intervals of dosing; and 2) Identify the persistence of induced biochemical and
structural deficits and AD pathology following termination of AβO infusion. These studies will utilize in-life (MRI)
and post-mortem measurements (immunohistochemistry, biochemistry) to establish the impact of AβOs
administration in the brain of the St. Kitts green monkey, a species that has been well characterized for its
propensity to develop naturally occurring features of AD pathology. The approach is innovative because it
represents a substantial shift from current AD research paradigms and tests a novel theoretical concept. The
research is significant because it is expected to overcome critical deficiencies in current animal AD models by
validating an accelerated, inducible NHP model of sporadic AD and permit effective translation of basic studies
into novel clinical diagnostic strategies and therapies. Success with this model development program would
provide a valuable resource to academic, biotechnology, pharmaceutical and diagnostic laboratories in need of
a reliable preclinical model of AD for basic research, and diagnostic and therapeutic development.
项目摘要
阿尔茨海默病(AD)患者的记忆和认知能力逐渐丧失,最终
丧失基本的身体功能和死亡。目前,65岁以上的美国人中有11%患有AD及其发病率,
医疗保健系统的费用继续上升,并产生重大的社会影响。没有治疗AD的方法
为了防止其不可阻挡的进程,开发AD新疗法的主要障碍是
现有的临床前建模不足,几乎完全涉及啮齿动物。作为非人类
灵长类动物(NHP)在所有方面都比啮齿类动物与人类具有更大的同源性,包括基因组学和
生理学,认知加工,神经网络复杂性,白色/灰质比率,
药物/靶点相互作用,以及年龄相关病理生理学的触发因素,本项目的长期目标
是开发一种新的AD NHP模型,该模型可以标准化并在严格的可重复研究中部署
克服当前将临床前研究转化为新型临床诊断策略的关键缺陷
和治疗。本申请的目的是扩大和推进最近的初步工作,
涉及鞘内给予淀粉样蛋白β-寡聚体(AβOs)的AD NHP模型。前提是
AβOs将引发一系列加速的病理学,模拟AD大脑中发生的变化。
患者这一假设是基于AD研究领域日益增长的共识,并得到了强有力的数据支持,
Aβ O很可能是一种有毒物质,它会引起血管中特有的缠结和斑块的沉积,
大脑突触和神经元的丧失以及相关的认知能力下降。假设是
通过追求以下两个具体目标,在统计学上有意义的设计中进行测试:1)确定
适当剂量的AβO和给药间隔; 2)确定诱导的生化和
终止AβO输注后的结构缺陷和AD病理学。这些研究将使用活体(MRI)
和死后测量(免疫组织化学、生物化学),以确定AβOs的影响
在圣基茨绿色猴的脑中施用,圣基茨猴是一种已被充分表征其
发展自然发生的AD病理特征的倾向。这种方法是创新的,因为它
代表了从当前AD研究范式的实质性转变,并测试了一个新的理论概念。的
研究是重要的,因为它有望克服目前动物AD模型的关键缺陷,
验证散发性AD的加速、诱导型NHP模型,并允许基础研究的有效转化
新的临床诊断策略和治疗方法。该模型开发计划的成功将
为学术、生物技术、制药和诊断实验室提供宝贵的资源,
为基础研究、诊断和治疗开发提供可靠的AD临床前模型。
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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Dustin Robert Wakeman其他文献
Dustin Robert Wakeman的其他文献
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{{ truncateString('Dustin Robert Wakeman', 18)}}的其他基金
Amyloid Beta Oligomer Induction of Alzheimer's Disease in Nonhuman Primates
淀粉样β寡聚体在非人灵长类动物中诱导阿尔茨海默氏病
- 批准号:
9407456 - 财政年份:2017
- 资助金额:
$ 4.9万 - 项目类别:
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