Modulation of autophagic flux as a therapeutic strategy for Alzheimer's disease
Modulation of autophagic flux as a therapeutic strategy for Alzheimer's disease
批准号:
10417514
负责人:
Swetha Gowrishankar
金额:
$177.38万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-05-15 至 2025-04-30
关键词:
APP-PS1Abeta clearanceAchievementAffectAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease patientAmyloidAmyloid beta-42AutophagocytosisAutophagosomeAxonBehaviorBiogenesisBiological AssayBiological ProcessBiologyClinicalCommunitiesComplexDefectDementiaDevelopmentDiseaseDisease ProgressionDrug KineticsExhibitsFDA approvedFRAP1 geneFemaleGliosisGoalsHomeostasisHumanIn VitroInduced pluripotent stem cell derived neuronsLeadLifeLongevityLysosomesMetabolismMissionModelingMusNatureNeurodegenerative DisordersNeuronsOrganellesPathologyPathway interactionsPatientsPersonsPharmaceutical PreparationsPhenotypePreparationPreventionProcessPropertyProteomicsPublic HealthQuality of lifeRecyclingResearchResolutionRoleSenile PlaquesSolubilityStructure-Activity RelationshipSymptomsTestingTherapeuticTherapeutic InterventionUnited StatesVesicleage related neurodegenerationamyloid precursor protein processinganalogblood-brain barrier penetrationcell injurydesigndisease phenotypedrug discoverydrug metabolismefficacy evaluationefficacy studyexperimental studyimprovedin vivoin vivo Modelinnovationlead optimizationmalemouse modelneuron lossnew therapeutic targetnovelnovel therapeuticspreventrestorationsexsmall moleculesymptom treatmenttargeted treatmenttherapeutic developmenttool
中文摘要
自噬是一种分解代谢的细胞循环过程,维持细胞内稳态,其失调具有重要的生物学意义
英文摘要
Autophagy is a catabolic cellular recycling process that maintains cellular homeostasis and its dysregulation has
been implicated in numerous diseases, including neurodegenerative diseases such as Alzheimer’s disease (AD).
AD is an age-related neurodegenerative disease that affects more than 5 million people in the United States.
Autophagic and lysosomal defects have been observed in AD, including accumulation of autophagic vesicles
and lysosomal intermediates as well as defective lysosomal processing of autophagosome contents. Small-
molecule autophagy activators that could overcome these defects could potentially halt disease progression
through the restoration of cellular homeostasis and the prevention of neuronal cell damage. Our central
hypothesis is that small-molecule autophagy activators will restore autophagic and lysosomal homeostasis and
exhibit neuroprotective effects that will prevent disease progression and ameliorate Alzheimer’s disease
symptoms in vivo. This hypothesis will be tested through the overall objectives of this proposal to optimize an
autophagy activator as an in vivo tool compound and drug lead and to evaluate the efficacy of autophagy
modulation for the resolution of AD phenotypes in disease-relevant assays and in vitro neuronal models as well
as an in vivo model. Our approach is innovative because we have identified mTOR-independent autophagy
activators and will identify and validate their unique targets and mechanisms of action in neuronal models to
potentially reveal new targets for AD drug discovery. The aims of this proposal will contribute to the achievement
of our long-term goal to develop new therapeutics for unmet needs in neurodegenerative diseases. FDA-
approved drugs for AD treat the symptoms of the disease but do not improve the underlying cell damage that
leads to disease progression, further highlighting the need for novel neuroprotective therapeutic options.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1091/mbc.e21-09-0473
发表时间:
2022-10-01
期刊:
MOLECULAR BIOLOGY OF THE CELL
影响因子:
3.3
作者:
[Majumder, Piyali, Edmison, Daisy, Rodger, Catherine, Patel, Sruchi, Reid, Evan, Gowrishankar, Swetha]
通讯作者:
Gowrishankar, Swetha
Elucidating the role of Adaptor Protein complex-4 in regulating axonal autophagic and lysosomal pathways
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批准号:10531491
-
项目类别:
-
资助金额:$53.32万
-
财政年份:2022
-
负责人:Swetha Gowrishankar
-
依托单位:
Elucidating the role of Adaptor Protein complex-4 in regulating axonal autophagic and lysosomal pathways
-
批准号:10700082
-
项目类别:
-
资助金额:$48.32万
-
财政年份:2022
-
负责人:Swetha Gowrishankar
-
依托单位:
海外基金