The hippocampal dentate gyrus in aging and Alzheimer's disease: boosting transcription of retinoic acid-sensitive genes through vitamin A supplementation and HDAC inhibition
衰老和阿尔茨海默病中的海马齿状回:通过补充维生素 A 和抑制 HDAC 来促进视黄酸敏感基因的转录
基本信息
- 批准号:10669202
- 负责人:
- 金额:$ 62.36万
- 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:2022-08-01 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAge-associated memory impairmentAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAntioxidantsAutopsyBehavioralBindingBiological AssayBiological AvailabilityClinical TrialsComplexDNADataDisease ProgressionEpigenetic ProcessFDA approvedGene Expression RegulationGene SilencingGenesGenetic TranscriptionHippocampusHistone DeacetylaseHistone Deacetylase InhibitorHormonesImpairmentKnowledgeLearningLigand BindingLigandsLipidsLongevityMediatingMemoryMethodsMultiomic DataOnset of illnessOutcome MeasureOxidative StressPredictive ValueProcessProteinsReactive Oxygen SpeciesRetinoic Acid ReceptorRetinoic Acid Response ElementRodentRoleSignal TransductionSupplementationTestingTimeTranscriptional RegulationTretinoinUp-RegulationVitamin Aage relatedbehavior testcell typedentate gyrusdietary antioxidantdrug repurposinggene repressioninnovationinterdisciplinary approachlipidomicsmetabolomicsmouse modelmultiple omicsnovel strategiesoxidative damagepredictive signaturepreventpublic health relevancesecondary analysistau Proteinstranscriptomicstranslational potential
项目摘要
PROJECT SUMMARY / ABSTRACT
The hippocampal dentate gyrus (DG), critically involved in learning and memory, is a vulnerable region in both
age-related cognitive impairment (ARCD) and Alzheimer’s disease (AD). Causal upstream signaling
mechanisms that lead to AD remain poorly understood. Across lifespan, excess reactive oxygen species (ROS)
accumulate, causing oxidative damage to proteins, lipids, and DNA. This process is termed oxidative stress
(OS). Dietary antioxidants (AOs) normally scavenge excess ROS, preventing OS. Moreover, OS triggers AO
defenses, which ultimately yield to AD progression. Yet, to date, clinical trials involving AO supplementation have
paradoxically failed, exposing large knowledge gaps in understanding which AO species are depleted, the time
course of AO depletion, and the underlying mechanisms. The AO all-trans retinoic acid (ATRA), a bioactive form
of Vitamin A (VA), serves a dual role as a ROS scavenger and hormone-like ligand for the retinoic acid receptor
(RAR). Ligand binding to RARs is critical for transcriptional regulation of genes containing retinoic acid response
elements (RAREs). Recent evidence from rodents has demonstrated an age-dependent homeostatic collapse
in hippocampal ATRA levels. Moreover, there is increasing evidence that transcriptional silencing occurs in AD.
To investigate ATRA depletion, we performed a secondary analysis of hippocampal transcriptomic data from
post-mortem AD brains. ATRA-sensitive genes were downregulated, accompanied by upregulation of RAR
repressors. Moreover, several histone deacetylases (HDACs) were upregulated, providing evidence for
epigenetic changes. Given this strong scientific premise, we hypothesize that both ATRA bioavailability and
HDAC inhibition are required to restore ATRA-mediated gene transcription and hippocampal-dependent
learning. Therefore, our central hypothesis is that combining vitamin A supplementation and HDAC inhibition
(HDACI) maintains hippocampal-dependent learning and RAR-sensitive gene transcription in DG more
effectively than HDACi alone. Using an innovative multidisciplinary approach, we will determine effects of
combining VA supplementation with HDAC inhibition on learning and transcription of RAR-sensitive genes in DG
cell types. SA1 tests the hypothesis that VA supplementation alleviates AD-related learning deficits and multi-
omic signatures in the DG. SA2 tests the hypothesis that HDAC inhibition alleviates AD-related learning deficits
and multi-omic signatures in the DG. SA3 tests the hypothesis that combining VA supplementation and HDAC
inhibition (VA+HDACI) synergistically alleviates AD-related learning deficits and multi-omic signatures in the DG
beyond VA and HDACI alone. Successful completion of this project will increase knowledge of aberrant
transcriptional mechanisms occurring in the DG during AD. Integrating behavioral and multi-omic data, the
project will elucidate multi-omic signatures in DG that protect against AD, enable the discovery of new genes
necessary for DG function, and determine the value of drug repurposing for an FDA- approved HDAC inhibitor.
项目摘要/摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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John Joshua Lawrence其他文献
John Joshua Lawrence的其他文献
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{{ truncateString('John Joshua Lawrence', 18)}}的其他基金
Transcriptional Dysfunction in Dentate Gyrus Cell Types: Roles of Retinoic Acid Responsive Genes in Protection Against Alzheimer's Disease Pathogenesis
齿状回细胞类型的转录功能障碍:视黄酸反应基因在预防阿尔茨海默病发病机制中的作用
- 批准号:
10367173 - 财政年份:2022
- 资助金额:
$ 62.36万 - 项目类别:
Transcriptional Dysfunction in Dentate Gyrus Cell Types: Roles of Retinoic Acid Responsive Genes in Protection Against Alzheimer's Disease Pathogenesis
齿状回细胞类型的转录功能障碍:视黄酸反应基因在预防阿尔茨海默病发病机制中的作用
- 批准号:
10543800 - 财政年份:2022
- 资助金额:
$ 62.36万 - 项目类别:
The hippocampal dentate gyrus in aging and Alzheimer's disease: boosting transcription of retinoic acid-sensitive genes through vitamin A supplementation and HDAC inhibition
衰老和阿尔茨海默病中的海马齿状回:通过补充维生素 A 和抑制 HDAC 来促进视黄酸敏感基因的转录
- 批准号:
10446664 - 财政年份:2022
- 资助金额:
$ 62.36万 - 项目类别:
Differential modes of cholinergic transmission onto cellular hippocampal targets
胆碱能传输到细胞海马靶标的不同模式
- 批准号:
9144946 - 财政年份:2015
- 资助金额:
$ 62.36万 - 项目类别:
Differential modes of cholinergic transmission onto cellular hippocampal targets
胆碱能传输到细胞海马靶标的不同模式
- 批准号:
8272674 - 财政年份:2010
- 资助金额:
$ 62.36万 - 项目类别:
Differential modes of cholinergic transmission onto cellular hippocampal targets
胆碱能传输到细胞海马靶标的不同模式
- 批准号:
8617333 - 财政年份:2010
- 资助金额:
$ 62.36万 - 项目类别:
Differential modes of cholinergic transmission onto cellular hippocampal targets
胆碱能传输到细胞海马靶标的不同模式
- 批准号:
8042776 - 财政年份:2010
- 资助金额:
$ 62.36万 - 项目类别:
Differential modes of cholinergic transmission onto cellular hippocampal targets
胆碱能传输到细胞海马靶标的不同模式
- 批准号:
8810769 - 财政年份:2010
- 资助金额:
$ 62.36万 - 项目类别:
Differential modes of cholinergic transmission onto cellular hippocampal targets
胆碱能传输到细胞海马靶标的不同模式
- 批准号:
8662325 - 财政年份:2010
- 资助金额:
$ 62.36万 - 项目类别:
Differential modes of cholinergic transmission onto cellular hippocampal targets
胆碱能传输到细胞海马靶标的不同模式
- 批准号:
8134323 - 财政年份:2010
- 资助金额:
$ 62.36万 - 项目类别:
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