Preclinical evaluation of tacrolimus in a canine model of Alzheimer's disease
他克莫司在阿尔茨海默病犬模型中的临床前评价
基本信息
- 批准号:10198086
- 负责人:
- 金额:$ 38.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-15 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:7 year old9 year oldAdverse effectsAgeAge-MonthsAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease therapeuticAlzheimer&aposs disease therapyAlzheimer’s disease biomarkerAmyloidAmyloid beta-ProteinAmyloid depositionAnimal ModelAnimalsAnti-Inflammatory AgentsAtrophicAttenuatedAutopsyBehavioralBiochemicalBiological AssayBiological MarkersBloodBrainCalcineurinCalcineurin inhibitorCanis familiarisCerebrospinal FluidCerebrovascular DisordersCerebrumClinical TrialsCognitionCognitiveDementiaDevelopmentDiffusion Magnetic Resonance ImagingDiseaseDoseElderlyExhibitsExperimental ModelsFDA approvedFK506FreezingFunctional disorderGeneral PopulationGenesGeneticGoldHumanHyperactivityImageImmuneImmunohistochemistryImpaired cognitionIncidenceIndividualInflammatoryInvestigationKidney TransplantationLabelLaboratoriesLiquid substanceLiteratureLongevityLongitudinal StudiesMagnetic Resonance ImagingMagnetic Resonance SpectroscopyMaintenanceMatched GroupMeasuresMetabolicMetabolic dysfunctionMetabolismModelingMolecularMolecular TargetMusNerve DegenerationNeuronsOralOral AdministrationOrgan TransplantationPPP3CA genePathologicPathologyPathway interactionsPerfusionPharmaceutical PreparationsPharmacologyPharmacotherapyPlacebosPlant RootsPre-Clinical ModelPreclinical TestingPredispositionPropertyProphylactic treatmentProtein phosphataseProteolysisRecoveryRodentRoleSafetySamplingSignal TransductionSolidSpin LabelsStandard ModelStructureSynapsesTacrolimusTestingTimeTransgenic MiceTransgenic OrganismsTranslationsTransplant RecipientsWorkabeta depositionallograft rejectionamyloid pathologybiobehaviorbrain metabolismbrain tissuecalcineurin phosphatasecell typecerebrovascularcerebrovascular imagingcerebrovascular pathologycognitive functioncytokinedruggable targetepidemiology studyfamilial Alzheimer diseaseglial activationimprovedmiddle agemouse modelmutantneurogenesisneuroimagingneuroinflammationneuron lossneuropathologyneurotoxicityoverexpressionpreclinical evaluationpreventrelating to nervous systemscreeningsynaptic functiontherapy designtreatment durationtreatment strategywhite matter
项目摘要
7. Project Summary/Abstract
This project uses aging beagles and a longitudinal treatment design to test the potential of a calcineurin (CN)
inhibiting strategy in Alzheimer's disease (AD). Beagles are metabolically similar to humans and spontaneously
develop amyloid-β (Aβ) deposition with advanced age. Consequently, the aging beagle model has shown
exceptional predictive validity in regard to several high-profile anti-AD drug trials. The molecular target of our
treatment strategy, CN, has recently emerged as a key mechanism for AD pathophysiology. Signs of CN
hyperactivity are found during early stages of cognitive decline in humans and in mouse models of AD. Studies
across numerous laboratories, using a variety of experimental models, suggest that CN activity is both
necessary and sufficient for the progression of key AD biobehavioral markers including Aβ deposition,
neurodegeneration, neuroinflammation/glial activation, synapse dysfunction, and cognitive loss. To inhibit CN,
we will use tacrolimus, an FDA-approved drug for the prophylaxis of allograft rejection and a second line
treatment for numerous immune/inflammatory disorders. In animal models, tacrolimus exhibits potent anti-
inflammatory, neuroprotective, and perhaps lifespan extending properties. Moreover, a recent epidemiological
study found that the incidence of dementia was strikingly reduced in human kidney transplant patients taking
tacrolimus, relative to age-matched subjects in the general population.
In this project, 5-6 month old beagles will undergo 1 year of behavioral/cognitive screening. At 6-7
months-of age (prior to the development of significant amyloid pathology), dogs will be sorted into two groups
matched for cognitive status. One group will received tacrolimus (.075mg/kg/day, orally) continuously for the
next two years, while the other group will receive placebo. Aim 1 will assess multidomain cognition and
measure blood and CSF biomarkers (e.g. Aβ and cytokines) at multiple time points across the tacrolimus
treatment period. Aim 2 will use MRI/MRS to measure longitudinal changes in cerebral perfusion, brain
metabolism, and structural integrity. Aim 3 will use immunohistochemistry and a variety of biochemical assays
to assess AD biomarkers (e.g. Aβ deposition, glial activation, synapse loss, and neurodegeneration) and CN-
related signaling parameters (e.g. cell-type specific expression, CN proteolysis, and NFAT activation) in
postmortem brain tissue. These studies will provide a rigorous test of the CN hypothesis of AD and possibly
pave the way for investigating CN inhibition has a primary or complimentary treatment strategy in human AD
clinical trials.
7.项目总结/摘要
该项目使用老化的比格犬和纵向治疗设计来测试钙调磷酸酶(CN)的潜力。
阿尔茨海默病(Alzheimer's disease,AD)的治疗策略。比格犬的代谢与人类相似,
随着年龄的增长,淀粉样蛋白-β(Aβ)沉积。因此,衰老的小猎犬模型表明,
在几项备受瞩目的抗AD药物试验中具有出色的预测效度。我们的分子靶点
治疗策略CN最近已成为AD病理生理学的关键机制。CN的标志
在人类和AD小鼠模型中认知衰退早期发现了活动过度。研究
在众多实验室中使用各种实验模型进行的研究表明,氯化萘的活性
对于关键AD生物行为标志物(包括Aβ沉积)的进展是必要和充分的,
神经变性、神经炎症/神经胶质活化、突触功能障碍和认知丧失。为了抑制CN,
我们将使用他克莫司,一种FDA批准的预防同种异体移植排斥反应的药物,
治疗多种免疫/炎症疾病。在动物模型中,他克莫司表现出有效的抗-
炎症性、神经保护性,也许还有延长寿命的特性。此外,最近流行的
一项研究发现,在人类肾移植患者中,
他克莫司,相对于一般人群中年龄匹配的受试者。
在这个项目中,5-6个月大的比格犬将接受1年的行为/认知筛查。在6-7
月龄时(在发生显著的淀粉样蛋白病理学之前),将狗分成两组
与认知状态匹配一组将连续接受他克莫司(0.075 mg/kg/天,口服),
在接下来的两年里,另一组将接受安慰剂。目标1将评估多领域认知,
在他克莫司治疗期间的多个时间点测量血液和CSF生物标志物(例如Aβ和细胞因子)
治疗期。目的2将使用MRI/MRS测量脑灌注、脑
新陈代谢和结构完整性。目的3将使用免疫组织化学和各种生化测定
评估AD生物标志物(例如Aβ沉积、神经胶质活化、突触丢失和神经变性)和CN-
相关的信号传导参数(例如细胞类型特异性表达、CN蛋白水解和NFAT活化),
死后的脑组织这些研究将为AD的CN假设提供严格的检验,
为研究CN抑制是否是人类AD的主要或补充治疗策略铺平道路
临床试验
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Tacrolimus Protects against Age-Associated Microstructural Changes in the Beagle Brain.
他克莫司可防止比格犬大脑中与年龄相关的微观结构变化。
- DOI:10.1523/jneurosci.0361-21.2021
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Radhakrishnan,Hamsanandini;Ubele,MargoF;Krumholz,StephanieM;Boaz,Kathy;Mefford,JenniferL;Jones,ErinDenhart;Meacham,Beverly;Smiley,Jeffrey;Puskás,LászlóG;Powell,DavidK;Norris,ChristopherM;Stark,CraigEL;Head,Elizabeth
- 通讯作者:Head,Elizabeth
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Elizabeth Head其他文献
Elizabeth Head的其他文献
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{{ truncateString('Elizabeth Head', 18)}}的其他基金
T21RS Meeting June 2022 Long Beach, California
T21RS 会议 2022 年 6 月 加利福尼亚州长滩
- 批准号:
10469127 - 财政年份:2022
- 资助金额:
$ 38.25万 - 项目类别:
Preclinical evaluation of tacrolimus in a canine model of Alzheimer's disease
他克莫司在阿尔茨海默病犬模型中的临床前评价
- 批准号:
10446042 - 财政年份:2017
- 资助金额:
$ 38.25万 - 项目类别:
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