Circadian Organization and Disorder in Alzheimer's Disease
阿尔茨海默病的昼夜节律组织和紊乱
基本信息
- 批准号:10447687
- 负责人:
- 金额:$ 40.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AlgorithmsAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease careAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease riskAmyloid beta-ProteinBehaviorBehavioralBiopsy SpecimenBrainBrain regionCaregiversCell NucleusCellsCessation of lifeChronotherapyCircadian DysregulationCircadian RhythmsCircadian desynchronyClinicalCollectionDataDatabasesDevelopmentDiseaseDisease PathwayDisease ProgressionDrug TargetingExhibitsFunctional disorderGenerationsGenesGenetic TranscriptionHumanIn VitroIndividualInflammationInformaticsKnowledgeMachine LearningMeasuresMethodsMolecularMolecular ProfilingMusNerve DegenerationNeurofibrillary TanglesNuclearParietal LobePathologyPathway interactionsPatientsPatternPeriodicityPharmaceutical PreparationsPhasePhysiologyPlayPopulationProteinsPublic HealthReportingResearchResearch DesignResearch PersonnelResourcesRoleSamplingSleepSleep DeprivationSleep Wake CycleSleep disturbancesSpecimenStructureSymptomsSynapsesTestingTherapeuticTimeTissuesTranscriptTranslationsUpdateWakefulnessWorkagedaging populationbasecell typecircadiancircadian biologycircadian transcriptomedisease-causing mutationexperienceexperimental studyfrontal lobegenetic varianthuman datahuman diseasehuman tissuemetabolomemind controlmolecular clockmultidimensional datanovelnovel therapeuticsprotein metaboliterelating to nervous systemrisk varianttau Proteinstooltranscriptome
项目摘要
ABSTRACT
With an aging population, the impact of Alzheimer's disease (AD) on public health continues to explode.
Altered daily rhythms in physiology and behavior are prominent features of AD. These altered activity rhythms
are difficult to treat, disrupting the lives of both patients and caregivers. Mounting evidence suggests that these
changes are more than just symptoms. Altered rhythms may contribute to AD progression and development.
Many important transcripts, proteins, and metabolites oscillate with a daily cycle. Understanding these
rhythms, and their influence on AD, offers the potential to identify new therapies.
The translation of circadian biology to Alzheimer's care is limited. Which molecules and pathways show daily
rhythms in our human brains? How do those rhythms change with AD? Do changes in molecular rhythms
explain changing behavioral patterns? Can these rhythms be exploited for therapeutic benefit?
To answer clinical questions, we need human data. AD brain banks provide an invaluable resource. But brain
banks almost never provide the time of day when patients died, making it difficult to use these data for rhythms
research.
We developed CYCLOPS (CYCLic Ordering by Periodic Structure), a machine-learning tool to uncover
molecular rhythms using unordered biopsy samples. Evaluating brain expression data, we showed that
CYCLOPS could correctly reconstruct rhythms in brain samples and correctly predict the time of death.
Here we will order cortical brain samples from control subjects and patients with AD. We will reconstruct the
molecular rhythms in these human brains, identifying differences in AD patients and rhythms in known drug
targets and AD disease pathways.
We will analyze a subset of samples where time of death is known, comparing each subject's “internal
molecular time” with the “time on the clock.” We will test the hypothesis that patients with poorly aligned
molecular rhythms are more likely to have circadian behavioral disturbance. We will evaluate a measure of
transcriptional rhythm strength, testing if “weaker” rhythms predict behavioral or molecular misalignment.
Does AD alter rhythm generation? Does it desynchronize still rhythmic cells and brain regions? Using data
from multiple brain regions sampled from the same subjects, we will evaluate intracortical circadian synchrony
and compare AD patients with controls. Using single-nucleus sequencing data, we will explore the effect of AD
on cell type specific rhythms and their synchrony. Finally, we will test the direct influence of important AD
causing mutations on molecular clock function, measuring rhythms in isolated cells.
This work will advance our understanding of circadian rhythms in AD pathology, clarify the relationship
between behavioral and molecular circadian disruption, and catalyze opportunities for AD chronotherapy.
摘要
随着人口老龄化,阿尔茨海默病(AD)对公共卫生的影响持续爆炸。
生理和行为的日常节律改变是AD的突出特征。这些改变的活动节奏
很难治疗,扰乱了患者和护理人员的生活。越来越多的证据表明,
变化不仅仅是症状。改变的节律可能有助于AD的进展和发展。
许多重要的转录物、蛋白质和代谢物以每天的周期振荡。了解这些
节律及其对AD的影响提供了识别新疗法的潜力。
昼夜节律生物学对阿尔茨海默氏症护理的翻译是有限的。哪些分子和途径每天显示
我们人类大脑的节奏这些节奏是如何随着AD而变化的?分子节奏的变化
解释行为模式的改变这些节律能被用于治疗吗?
为了回答临床问题,我们需要人类数据。AD大脑银行提供了宝贵的资源。但大脑
银行几乎从不提供患者死亡的时间,这使得很难将这些数据用于节律
research.
我们开发了CYCLOPS(周期性结构的循环排序),这是一个机器学习工具,可以揭示
使用无序活检样本的分子节律。通过评估大脑表达数据,我们发现,
CYCLOPS可以正确地重建大脑样本中的节律,并正确地预测死亡时间。
在这里,我们将订购对照组和AD患者的大脑皮质样本。我们将重建
这些人脑中的分子节律,识别AD患者的差异和已知药物的节律,
目标和AD疾病途径。
我们将分析死亡时间已知的样本子集,比较每个受试者的“内部”,
分子时间”和“时钟上的时间”我们将检验以下假设:
分子节律更可能具有昼夜行为紊乱。我们将评估
转录节奏强度,测试是否“较弱”的节奏预测行为或分子失调。
AD是否改变节律生成?它会使静止的节律细胞和大脑区域去兴奋化吗?使用数据
我们将从同一受试者的多个大脑区域采样,评估皮质内昼夜节律同步性
并将AD患者与对照组进行比较。使用单核测序数据,我们将探索AD的影响
细胞类型的特定节奏及其同步性。最后,我们将测试重要广告的直接影响
导致分子钟功能突变,测量孤立细胞的节律。
这项工作将促进我们对AD病理学中昼夜节律的理解,阐明其与AD发病的关系,
行为和分子昼夜节律破坏之间的联系,并催化AD时间疗法的机会。
项目成果
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Ron C. Anafi其他文献
Modeling the Response of Airway Smooth Muscle to Cyclic Loading
- DOI:
10.1016/j.bpj.2008.12.3272 - 发表时间:
2009-02-01 - 期刊:
- 影响因子:
- 作者:
Sharon R. Bullimore;Anne-Marie Lauzon;Antonio Z. Politi;Ron C. Anafi;James Sneyd;Jason H.T. Bates - 通讯作者:
Jason H.T. Bates
Ron C. Anafi的其他文献
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{{ truncateString('Ron C. Anafi', 18)}}的其他基金
Circadian Organization and Disorder in Alzheimer's Disease
阿尔茨海默病的昼夜节律组织和紊乱
- 批准号:
10046080 - 财政年份:2020
- 资助金额:
$ 40.45万 - 项目类别:
Circadian Organization and Disorder in Alzheimer's Disease
阿尔茨海默病的昼夜节律组织和紊乱
- 批准号:
10220845 - 财政年份:2020
- 资助金额:
$ 40.45万 - 项目类别:
Circadian Organization and Disorder in Alzheimer's Disease
阿尔茨海默病的昼夜节律组织和紊乱
- 批准号:
10667664 - 财政年份:2020
- 资助金额:
$ 40.45万 - 项目类别:
Integrated Informatic and Experimental Evaluations of Cancer Chronotherapy
癌症时间疗法的综合信息学和实验评估
- 批准号:
10636791 - 财政年份:2019
- 资助金额:
$ 40.45万 - 项目类别:
Integrated Informatic and Experimental Evaluations of Cancer Chronotherapy
癌症时间疗法的综合信息学和实验评估
- 批准号:
10379304 - 财政年份:2019
- 资助金额:
$ 40.45万 - 项目类别:
Integrated Informatic and Experimental Evaluations of Cancer Chronotherapy
癌症时间疗法的综合信息学和实验评估
- 批准号:
9906199 - 财政年份:2019
- 资助金额:
$ 40.45万 - 项目类别: