Understanding the Neuroprotective Activities of Posiphen
Understanding the Neuroprotective Activities of Posiphen
批准号:
8692627
负责人:
KUMAR SAMBAMURTI
金额:
$18.69万
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
已结题
起止时间:
2013-07-15 至 2017-04-30
关键词:
5&apos Untranslated RegionsA MouseAgeAge-MonthsAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease riskAmyloidAmyloid ProteinsAmyloid beta-ProteinAmyloid beta-Protein PrecursorAmyloid depositionAmyloidosisAnimal ModelAnimalsBehaviorBioavailableBiological MarkersBiological PreservationBrainCanis familiarisCell Culture TechniquesCholinesterasesChromosomes, Human, Pair 16Chromosomes, Human, Pair 17Chromosomes, Human, Pair 21ClinicalClinical Drug DevelopmentCognitionDementiaDepositionDeteriorationDoseDown SyndromeDrug DesignDrug TargetingEventExhibitsFailureFutureGenetic TranslationGoalsHomeostasisHumanHuman ChromosomesHyperhomocysteinemiaImmunotherapyImpaired cognitionImpairmentIndividualInstitutesInterventionLesionLifeMeasuresMediatingMetabolic PathwayMethodsModelingMusMutationNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNeuronal DysfunctionNeuronsOral AdministrationPathogenesisPathologyPatientsPhase I Clinical TrialsPhenotypePlasmaPresenile Alzheimer DementiaPropertyProtein BiosynthesisProteinsReducing AgentsRisk FactorsRodentRoleSenile PlaquesTartratesTestingTherapeuticTimeToxic effectTransgenic MiceTranslationsWeaningamyloid pathologybasal forebrain cholinergic neuronscholinergicfamilial Alzheimer diseasegamma secretasegrasphypercholesterolemiaimprovedmouse Ts65Dnmouse modelneuron lossneuropathologyneuroprotectionnovelphenserinepresenilinpreventprotein expressionpublic health relevancesecretasesmall moleculetau Proteinstheoriestool
中文摘要
描述(由申请人提供):唐氏综合症(DS)患者在生命早期表现为阿尔茨海默病(AD)神经病理,并在第四或第五个十年发展为进行性认知障碍。表达淀粉样β蛋白(A?)前体(APP)的转基因小鼠沉积淀粉样蛋白,但不呈现退化表型。DS的小鼠模型Ts65Dn小鼠患有许多神经元亚型的退化,包括在AD中丢失的基底前脑胆碱能神经元。这似乎需要APP复制,尽管高APP不足以在转基因小鼠中诱导神经退化。我们之前发现了一种新的化合物-Posiphen-通过调节APP的5‘非翻译区来抑制APP的翻译。我们正计划通过用Posiphen治疗动物模型来减少APP的表达,以确定长期治疗是否会出现类似AD的病理变化,以及这种治疗是否可以防止DS的神经退行性变。Ts65Dn小鼠的神经变性似乎依赖于APP,这使其成为评估抗APP疗法神经保护的有用模型。这个R21项目将检验这样一个假设,即APP合成的减少将恢复这种高表达蛋白质的动态平衡,从而防止DS小鼠的神经元丢失和行为。第二个假设是,泊西芬治疗将减少淀粉样斑块的堆积。在未来的研究中,我们计划继续与奈杰尔·格雷格博士合作进行药物的临床开发。该项目的两个具体目标是:1)评估Posiphen对Ts65Dn小鼠的治疗效果,Ts65Dn小鼠自然表达1.5倍以上的APP,并随着年龄的增长积累分泌的APP衍生物;2)确定Posiphen对转基因小鼠淀粉样蛋白沉积的影响。我们假设该治疗将成功地减少DS小鼠模型中的神经变性,并为我们提供工具来识别可能作为干预目标的晚期和窗口期。
英文摘要
DESCRIPTION (provided by applicant): Individuals with Down syndrome (DS) exhibit Alzheimer's disease (AD) neuropathology early in life, and develop progressive cognitive impairment in their fourth or fifth decade. Transgenic mice expressing Amyloid beta protein (A¿) precursor (APP) deposit amyloid but do not present degeneration phenotypes. A mouse model of DS, the Ts65Dn mice, suffers degeneration of a number of neuronal subtypes, including the basal forebrain cholinergic neurons that are lost in AD. This appears to require APP duplication although high APP is not sufficient to induce neurodegeneration in transgenic mice. We previously identified a novel compound - Posiphen - that inhibits APP translation by regulating the 5'-untranslated region of APP. We are planning to reduce APP expression by treating animal models with Posiphen to determine whether long-term treatment could arrent AD like pathology and if neurodegeneration in DS can be prevented by this treatment. The neurodegeneration in the TS65Dn mice appears to depend on APP making it a useful model to evaluate neuroprotection by anti-APP therapies. This R21 project will test the hypothesis that reduction of APP synthesis will restore homeostasis of this highly expressed protein and therefore prevent neuronal loss and behavior in DS mice. The second hypothesis is that Posiphen treatment will reduce amyloid accumulation as plaques. In future studies, we plan to continue collaborating with Dr. Nigel Greig for clinical development of the drug. The two specific aims of the project are: 1) Evaluate the effects of Posiphen treatment in the TS65Dn mice, which naturally express 1.5 times higher levels of APP and accumulate secreted APP derivatives with age; 2) Determine the effect of Posiphen on amyloid deposition in transgenic mouse models. We hypothesize that the treatment will successfully reduce neurodegeneration in the DS mouse model and provide us with the tools to identify the late and windows that may be targeted for intervention.
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批准号:9905467
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项目类别:
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资助金额:$18.69万
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财政年份:2019
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负责人:KUMAR SAMBAMURTI
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依托单位:
Understanding the Neuroprotective Activities of Posiphen
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批准号:8573968
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项目类别:
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资助金额:$22.43万
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财政年份:2013
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Regulation and Cell Biology of Beta-Secretase
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批准号:6831156
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资助金额:$23.94万
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财政年份:2004
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负责人:KUMAR SAMBAMURTI
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依托单位:
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批准号:7446704
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资助金额:$22.25万
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财政年份:2004
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Regulation and Cell Biology of Beta-Secretase
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批准号:6948204
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资助金额:$23.94万
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财政年份:2004
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负责人:KUMAR SAMBAMURTI
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依托单位:
Regulation and Cell Biology of Beta-Secretase
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批准号:7090062
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资助金额:$23.38万
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Regulation and Cell Biology of Beta-Secretase
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批准号:7257057
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资助金额:$22.7万
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依托单位:
Cholesterol and amyloidogenesis
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批准号:7059414
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项目类别:
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资助金额:$35.41万
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财政年份:2003
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负责人:KUMAR SAMBAMURTI
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依托单位:
Cholesterol and amyloidogenesis
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批准号:7258826
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项目类别:
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资助金额:$34.38万
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财政年份:2003
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负责人:KUMAR SAMBAMURTI
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依托单位:
NOVEL APPROACH FOR EXPRESSION CLONING OF APP SECRETASES
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项目类别:
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资助金额:$7.05万
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财政年份:1997
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负责人:KUMAR SAMBAMURTI
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依托单位:
海外基金