Discovery of functionally selective Alzheimer's disease therapeutics
发现功能选择性阿尔茨海默病疗法
基本信息
- 批准号:9754738
- 负责人:
- 金额:$ 54.46万
- 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:APP-PS1Activities of Daily LivingAddressAdrenergic AgentsAffinityAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmyloidAmyloid beta-ProteinBehavioralBiological AssayBiological MarkersBrainBrain-Derived Neurotrophic FactorCYP2D6 geneCYP3A4 geneCaregiver BurdenCaringCellsChronicCognitiveCognitive deficitsDementiaDepositionDevelopmentDevelopment PlansDiseaseDisease ProgressionDopamineDopamine D2 ReceptorDoseDrug InteractionsEncephalitisEvaluationFamilyFinancial HardshipFriendsFutureGenerationsGoalsHalf-LifeHaloperidolHistologicHourHydrogen PeroxideImpairmentInflammationInflammatoryInterruptionLeadLiver MicrosomesMeasurableMeasuresMediatingMedicalMedicareMedicineMemoryMetabolicModelingMolecular ChaperonesMusMuscarinic Acetylcholine ReceptorNerve DegenerationNeurogliaNeuronsNitratesNitric OxideOralOral AdministrationOxidative StressParentsPathogenicityPathologyPatientsPeroxonitritePharmaceutical ChemistryPharmaceutical PreparationsPharmacotherapyPlasmaPrevalencePrimatesProcessPropertyProteinsPurinergic P1 ReceptorsRecoveryResearchRodentSelection CriteriaSerotoninStressSuperoxidesSymptomsSynapsesTherapeuticToxic effectTransgenic MiceUnited Statesabeta depositionabeta oligomerage relatedbasebehavior testcannabinoid receptorcerebral atrophycognitive performancecytotoxicdose informationdrug developmentdrug testingentorhinal cortexhyperphosphorylated tauimprovedin vivoinnovationlead candidatemild cognitive impairmentmouse modelneuroinflammationnitrationnitrosative stressnon-drugpreventprogressive neurodegenerationprotein biomarkersreceptorresiliencescreeningsigma-1 receptortau Proteinstau aggregation
项目摘要
Abstract
The prevalence of Alzheimer's disease (AD) and the associated financial and caregiver burden is projected to escalate
dramatically unless disease-modifying treatments are discovered. Our research is focused on addressing this urgent unmet
medical and societal need through the discovery and development of pharmacotherapies capable of averting or delaying
the progression of AD. Brain inflammation initiated by chronic oxidative-nitrosative stress is a proven component of the
pathogenic cascade leading to mild cognitive impairment (MCI) and AD. When surplus inflammatory nitric oxide and
superoxide molecules combine they form the brain-impairing reactive species peroxynitrite. This perpetuates
inflammation resulting in the progressive neurodegeneration observed in AD. Our innovative approach consists of
managing two processes associated with inflammatory disease progression. The first involves interrupting the cycle of
peroxynitrite generation by suppressing unsafe elevations in nitric oxide triggered by oxidative stress, and the second
involves enhancing resilience to and recovery from inflammatory insults by facilitating the secretion of brain-derived
neurotrophic factor (BDNF). A single stress-activated chaperone protein is mechanistically capable of both mediating
BDNF secretion and regulating nitric oxide levels under proinflammatory conditions. Preliminary studies have identified
chemotype starting points for further CNS drug development which have the desired dual functional selectivity profile for
this target receptor. Our plan is to optimize the CNS drug-like properties of these functionally selective chemotypes with
the goal of developing medicines that can significantly modify the course of MCI/AD.
摘要
项目成果
期刊论文数量(0)
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ROBERT R LUEDTKE其他文献
ROBERT R LUEDTKE的其他文献
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{{ truncateString('ROBERT R LUEDTKE', 18)}}的其他基金
D3 Receptor Compounds for the Treatment of Psychostimulant Abuse
用于治疗精神兴奋剂滥用的 D3 受体化合物
- 批准号:
7676618 - 财政年份:2007
- 资助金额:
$ 54.46万 - 项目类别:
D3 Receptor Compounds for the Treatment of Psychostimulant Abuse
用于治疗精神兴奋剂滥用的 D3 受体化合物
- 批准号:
8069685 - 财政年份:2007
- 资助金额:
$ 54.46万 - 项目类别:
D3 Receptor Compounds for the Treatment of Psychostimulant Abuse
用于治疗精神兴奋剂滥用的 D3 受体化合物
- 批准号:
8135269 - 财政年份:2007
- 资助金额:
$ 54.46万 - 项目类别:
D3 Receptor Compounds for the Treatment of Psychostimulant Abuse
用于治疗精神兴奋剂滥用的 D3 受体化合物
- 批准号:
7676010 - 财政年份:2007
- 资助金额:
$ 54.46万 - 项目类别:
D3 Receptor Compounds for the Treatment of Psychostimulant Abuse
用于治疗精神兴奋剂滥用的 D3 受体化合物
- 批准号:
7842065 - 财政年份:2007
- 资助金额:
$ 54.46万 - 项目类别:
D3 Receptor Compounds for the Treatment of Psychostimulant Abuse
用于治疗精神兴奋剂滥用的 D3 受体化合物
- 批准号:
9011513 - 财政年份:2007
- 资助金额:
$ 54.46万 - 项目类别:
D3 Receptor Compounds for the Treatment of Psychostimulant Abuse
用于治疗精神兴奋剂滥用的 D3 受体化合物
- 批准号:
7346814 - 财政年份:2007
- 资助金额:
$ 54.46万 - 项目类别:
D3 Receptor Compounds for the Treatment of Psychostimulant Abuse
用于治疗精神兴奋剂滥用的 D3 受体化合物
- 批准号:
7501481 - 财政年份:2007
- 资助金额:
$ 54.46万 - 项目类别:
D3 Receptor Compounds for the Treatment of Psychostimulant Abuse
用于治疗精神兴奋剂滥用的 D3 受体化合物
- 批准号:
7919465 - 财政年份:2007
- 资助金额:
$ 54.46万 - 项目类别:
D3 Receptor Compounds for the Treatment of Psychostimulant Abuse
用于治疗精神兴奋剂滥用的 D3 受体化合物
- 批准号:
9185279 - 财政年份:2007
- 资助金额:
$ 54.46万 - 项目类别:
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