Identification and confirmation of blood-brain barrier (BBB) permeability of chemical enhancers of nerve growth factor-dependent neurite outgrowth.
Identification and confirmation of blood-brain barrier (BBB) permeability of chemical enhancers of nerve growth factor-dependent neurite outgrowth.
批准号:
9211354
负责人:
Gordon C Ibeanu
金额:
$10.8万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-02-01 至 2020-01-31
关键词:
AffectAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAnimal ModelArchitectureAxonBasal Nucleus of MeynertBiological AssayBloodBlood - brain barrier anatomyBrainCell DeathCell modelCell physiologyCellsChemical StructureChemicalsChemosensitizationComplexComputer SimulationCuesDataDefectDeteriorationDevelopmentEnhancersExhibitsFutureGoalsGrowthHippocampus (Brain)Huntington DiseaseImageIn VitroLaboratoriesLeadLibrariesLinkLiteratureMaintenanceMedicalMethodologyMorphologyMusNatural ProductsNerve Growth FactorsNeuritesNeurodegenerative DisordersNeuronsNeuropeptidesOxidative StressParkinson DiseasePathway interactionsPatientsPeptidesPerinatalPermeabilityPharmaceutical PreparationsPharmacologyPhenotypePlantsPopulationPositioning AttributeProbabilityProcessPropertyProsencephalonProteinsRecombinantsRecovery of FunctionRegulationReportingResearchRoleSchemeSensorySeriesSignal PathwaySignal TransductionSmall Molecule Chemical LibraryStructureSynapsesTestingTherapeuticTherapeutic AgentsThiophenesToxic effectTransgenic OrganismsVerbenaVertebral columnage relatedanalogbasecholinergicdirect applicationimprovedin vivolead seriesmemory acquisitionnerve supplyneuron lossneurotrophic factornovelnovel therapeuticsprogramspublic health relevanceresponserestorationscaffoldscreeningsmall moleculetooltransmission process
中文摘要
英文摘要
DESCRIPTION (provided by applicant): Nerve cell death is a gross neuropathologic feature associated with many neurodegenerative diseases. In the case of Alzheimer's disease (AD), deterioration of synaptic connections made by axons and dendritic processes has been linked to the loss of neurotrophic support in the brain centers affected by AD. Several experimental strategies and discovery schemes have been employed as a means to reverse the effects on neuronal architecture but many have not translated into successful therapies. Direct application of nerve growth factor (NGF) has been shown to augment morphological and sometimes functional recovery of degenerating neurons suggesting that a therapeutic approach that enhances the function of neurotrophins could halt or reverse the effects of AD and other neurodegenerative diseases. Our central hypothesis is that small molecules that enhance the activities of neurotrophins are uniquely suited to study the fundamental mechanisms that underlie activity potentiation of neuropeptides by drug-like chemicals in order to identify potentil targets that could lead to development of novel therapeutics for many age-related neurodegenerative diseases. Consequently, we have synthesized and tested Verbenachalcone (VC), a natural product from Verbena litoralis, and several derivatives that promote neurite outgrowth (NOG) in neuronal cell models. In addition, we utilized the dihydrochalcone backbone of VC as a template in a computational model to identify a small molecule B355252 with NGF-dependent NOG promoting activity and neuroprotective properties. Derivatives of the small molecule with improved toxicity profile have been synthesized. However, the SAR studies have not yielded improvements in compound potency. In this project we propose to identify compounds with novel scaffolds different from that of B355252, which synergize with NGF to enhance NOG by implementing a phenotypic image-based screen. In addition, we will develop and validate an in vitro blood- brain permeability assay to test the analogs and hits from the screen for potential to cross the blood-brain barrier and initiate studies on the signaling mechanisms of lead compounds as a prelude for future in vivo compound studies.
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会议论文
Identification of Small Molecule Ligands with NGF Potentiating Activity
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批准号:7903839
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项目类别:
-
资助金额:$22.03万
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财政年份:2009
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负责人:Gordon C Ibeanu
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依托单位:
Identification of Small Molecule Ligands with NGF Potentiating Activity
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批准号:7500069
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项目类别:
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资助金额:$10.24万
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财政年份:2007
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负责人:Gordon C Ibeanu
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依托单位:
Identification of Small Molecule Ligands with NGF Potentiating Activity
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批准号:7916674
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项目类别:
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资助金额:$10.28万
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财政年份:2007
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负责人:Gordon C Ibeanu
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依托单位:
Identification of Small Molecule Ligands with NGF Potentiating Activity
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批准号:7683033
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项目类别:
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资助金额:$9.84万
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财政年份:2007
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负责人:Gordon C Ibeanu
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依托单位:
Identification of Small Molecule Ligands with NGF Potentiating Activity
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批准号:7288985
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项目类别:
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资助金额:$10.33万
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财政年份:2007
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负责人:Gordon C Ibeanu
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依托单位:
海外基金