AMPK localization, expression, and activity in Alzheimer's Disease
AMPK 在阿尔茨海默病中的定位、表达和活性
基本信息
- 批准号:10537142
- 负责人:
- 金额:$ 4.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAdenosine MonophosphateAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease patientAmericanAmyloidAutomobile DrivingAutopsyBiochemicalBioinformaticsBrainBrain regionCell Culture TechniquesCell NucleusCellular biologyClinicalClinical TrialsComplementConsensusDataData SetDementiaDiseaseDisease ProgressionEnzymesFellowshipFunctional disorderGoalsHippocampus (Brain)HomeostasisHumanIn VitroIndividualInduced pluripotent stem cell derived neuronsLiteratureMeasuresMentorsMetabolicMetabolic dysfunctionMetabolismMitochondriaNerve DegenerationNeuronsNuclearPathogenesisPathologicPatternPharmaceutical PreparationsPhenotypePhosphotransferasesPlayPopulationPrefrontal CortexPreparationPrevalenceProtein IsoformsProtein KinasePublic HealthRegulationResearchRoleSamplingScientistSignal TransductionSynapsesTechniquesTestingTrainingUnited Statesbasecareercell typedisease phenotypeeffective therapyexperienceexperimental studygenetic manipulationhuman old age (65+)in silicoin vivoinduced pluripotent stem cellinsightmild cognitive impairmentnovelnovel therapeuticsoverexpressionpre-clinicalprospectiveproteostasisstem cellssynaptic functiontau phosphorylationtissue processingtranscriptomicstranslational physician
项目摘要
PROJECT SUMMARY. Alzheimer’s disease (AD) is the most common cause of dementia and it is estimated
that one in ten Americans aged 65 and older has AD. The number of Americans with Alzheimer’s will escalate
rapidly in coming years as the size and proportion of the U.S. population aged 65 and older increases. With no
disease-altering or curative drugs available, and with more than 140 failed clinical trials, AD has become a major
public health concern. There is a consensus that a deeper understanding of the pathophysiology of this
devastating illness is needed to move the field forward. The amyloid-cascade hypothesis has been the leading
theoretical construct guiding our understanding of the pathophysiology of AD for the past thirty years. However,
this construct has overlooked the multifaceted cellular mechanisms that ultimately drive neurodegeneration and
the subsequent clinical manifestations of the disease. It has been hypothesized that aberrant metabolic signaling
is a major cellular mechanism driving AD. These metabolic perturbations may arise through the dysfunction of
adenosine monophosphate activated protein kinase (AMPK). AMPK is the master regulator of cellular energy
status. Despite its strong association with AD, AMPK has not been fully characterized in AD: it is unknown how
the subcellular localization, activity, and expression are changed in vulnerable regions of the human AD brain.
Pre-clinical literature implicates AMPK in the regulation of synaptic function, A metabolism, tau phosphorylation,
and pathologic proteostasis in AD. AMPK is an obligatory heterotrimer composed of catalytic () and regulatory
( and ) subunits. While the subunit has been functionally characterized in AD models, the role of the
regulatory subunits is unknown. As such, a functional understanding of this kinase in human substrates is
missing. The central hypothesis of this proposal is that nuclear AMPK activity and localization is decreased in
AD. We will test this hypothesis by using postmortem dorsolateral prefrontal cortex and hippocampus from mild
cognitive impairment and AD subjects to analyze changes of AMPK as the disease progresses (Specific Aim 1).
In parallel, we will employ an omics platform to specifically complement our biochemical studies. Further, we will
use cortical neurons derived from AD-patient iPSCs to evaluate the role of the overlooked regulatory AMPK1
subunit in modulating a metabolic and synaptic phenotype (Specific Aim 2). This proposal addresses a critical
need to resolve the role of AMPK in the pathophysiology of this disorder. This research, in conjunction with the
experienced mentoring team, will provide this prospective Fellow an excellent training experience. Specifically,
this F30 Fellowship will support the applicant in gaining expertise in cell biology, bioinformatics, stem cell culture,
gene-manipulation strategies, and postmortem tissue processing, in preparation for a career as a translational
physician-scientist.
项目总结。据估计,阿尔茨海默病(AD)是痴呆症最常见的原因
项目成果
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Nicholas Daniel Henkel其他文献
Nicholas Daniel Henkel的其他文献
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{{ truncateString('Nicholas Daniel Henkel', 18)}}的其他基金
AMPK localization, expression, and activity in Alzheimer's Disease
AMPK 在阿尔茨海默病中的定位、表达和活性
- 批准号:
10728334 - 财政年份:2022
- 资助金额:
$ 4.06万 - 项目类别:
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