Dissecting Causal Role of Insomnia in Cardiovascular Disease
剖析失眠与心血管疾病的因果关系
基本信息
- 批准号:10621177
- 负责人:
- 金额:$ 74.98万
- 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:2020-05-15 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AtherosclerosisBehaviorBiologicalCRISPR/Cas technologyCardiovascular DiseasesCardiovascular PhysiologyCardiovascular systemClinical TrialsCluster AnalysisCodeCoronary ArteriosclerosisDataDiseaseDrosophila genusEtiologyFunctional disorderFutureGene Expression ProfileGene TargetingGenesGeneticGenetic studyGenetsGoalsHeart AbnormalitiesHematopoiesisHumanHuman GeneticsImmunityIncidenceInterventionKnock-inLeadLife StyleLinkMapsMechanicsMendelian randomizationModelingMusNational Heart, Lung, and Blood InstituteOrthologous GeneOutcomeParticipantPathway AnalysisPathway interactionsPatient Self-ReportPersonsPhenotypePopulationProteomicsRNA InterferenceResearchRiskRoleSamplingSleepSleep DisordersSleep disturbancesSleeplessnessSymptomsTestingTherapeuticTime-restricted feedingTissuesTrans-Omics for Precision MedicineWorkbiobankcardiovascular disorder riskcausal variantcohortcost efficientdesigneffective therapyexome sequencingflygenome sequencinggenome wide association studygenome-widegenomic locushuman diseaseimprovedimprovement on sleepknock-downloss of functionmetabolomicsmodel organismmulti-ethnicmultiple omicsnew therapeutic targetpolygenic risk scorepreclinical studypreventrare variantsmall moleculetherapeutic evaluationtraittranscriptomics
项目摘要
Project Summary/Abstract
Insomnia disorder occurs in 10-20% of the population and confers a >2-fold increased causal risk of incident
cardiovascular disease (CVD) based on our recent Mendelian randomization studies. To identify new therapeutic
targets for insomnia that ameliorate CVD risk, it is important to dissect the causal pathophysiology of insomnia
and distinguish whether increased CVD risk arises from shared causal mechanisms or specific cardiovascular
insults induced by the insomnia state. This proposal is motivated by the research question: how does insomnia
lead to increased CVD and what specific mechanisms of insomnia should be targeted to prevent or delay CVD?
We found 57 genome-wide significant genetic loci for insomnia and established robust causal links with CVD,
but need improved understanding of specific shared causal pathways and mechanistic links in order to move
towards personalized, effective therapies. Recent model organism studies describe specific mechanistic links
between sleep, immunity, atherosclerosis and cardiovascular disease that we can also test for disease relevance
in people to decipher convergent mechanisms. Thus, here we propose to leverage genome-sequencing and
integrative multi-omics in multi-ethnic samples from TopMed and exome sequencing in UK Biobank with focused
functional studies of sleep and cardiovascular function in Drosophila to find the causal genes and identify
mechanisms that causally link insomnia to CVD. We propose the following Specific Aims: 1) To pinpoint causal
genes at 57 established insomnia genetic loci and dissect underlying disease mechanisms and pathways in
humans (NHLBI TopMed and UK Biobank). Multi-ethnic fine-mapping and rare variant analysis will pinpoint
causal genes and soft clustering analysis informed by multi-trait associations will identify heterogeneous
insomnia disease mechanisms and subtypes. 2) To test the consequence of the loss of function of the Drosophila
orthologs of causal human insomnia genes on sleep and cardiovascular function. Phenotypic effects and gene
expression patterns will be systematically characterized to unravel important functional pathways and networks.
3) To test the impact of perturbed sleep (disrupted or improved) on incidence and progression of CVD in
Drosophila using small molecule-, genetic- mechanical perturbation and time-restricted feeding and using
integrative multi-omics in humans (NHLBI TopMed). Our project will shortlist therapeutically-relevant genes and
pathways that link insomnia, sleep and CVD.
项目总结/摘要
在10-20%的人群中发生胰岛素抵抗障碍,并使事件的因果风险增加2倍以上。
心血管疾病(CVD)的基础上,我们最近的孟德尔随机研究。寻找新的治疗方法
失眠的目标是改善心血管疾病的风险,重要的是要解剖失眠的因果病理生理学
并区分CVD风险增加是否由共同的因果机制或特定的心血管疾病引起,
由失眠状态引起的侮辱。这个提议是由研究问题激发的:失眠是如何
导致心血管疾病的增加,失眠的具体机制应该针对什么来预防或延迟心血管疾病?
我们发现了57个基因组范围内的失眠症重要遗传位点,并建立了与CVD的强有力的因果关系,
但需要更好地理解特定的共同因果途径和机制联系,
个性化的有效治疗最近的模式生物研究描述了特定的机制联系
睡眠、免疫力、动脉粥样硬化和心血管疾病之间的联系,我们也可以测试疾病的相关性,
来破译聚合机制因此,在这里,我们建议利用基因组测序,
来自TopMed的多种族样本中的整合多组学和英国生物库中的外显子组测序,
果蝇睡眠和心血管功能的功能研究,以找到致病基因,并确定
将失眠与心血管疾病联系起来的机制。我们提出以下具体目标:1)查明因果关系
基因在57个建立失眠遗传位点和解剖潜在的疾病机制和途径,
人类(NHLBI TopMed和UK Biobank)。多种族精细绘图和罕见变异分析将查明
通过多性状关联的因果基因和软聚类分析,
失眠症的发病机制及亚型。2)为了测试果蝇功能丧失的后果,
人类失眠症致病基因的直系同源物对睡眠和心血管功能的影响表型效应和基因
表达模式将被系统地表征,以揭示重要的功能途径和网络。
3)为了测试睡眠紊乱(中断或改善)对CVD发生率和进展的影响,
果蝇使用小分子、遗传-机械扰动和时间限制的进食和使用
人类整合多组学(NHLBI TopMed)。我们的项目将筛选出与治疗相关的基因,
失眠、睡眠和心血管疾病之间的联系。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Genetic evidence for a potential causal relationship between insomnia symptoms and suicidal behavior: a Mendelian randomization study.
- DOI:10.1038/s41386-022-01319-z
- 发表时间:2022-08
- 期刊:
- 影响因子:7.6
- 作者:Nassan, Malik;Daghlas, Iyas;Winkelman, John W.;Dashti, Hassan S.;Saxena, Richa
- 通讯作者:Saxena, Richa
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Girish C. Melkani其他文献
Time-restricted feeding mediated synchronization of circadian rhythms to sustain cardiovascular health
限时进食介导生物钟节律的同步以维持心血管健康
- DOI:
10.1016/j.yjmcc.2025.07.007 - 发表时间:
2025-09-01 - 期刊:
- 影响因子:4.700
- 作者:
Girish C. Melkani - 通讯作者:
Girish C. Melkani
Linkage of circadian rhythm disruptions with Alzheimer's disease and therapeutic interventions
昼夜节律紊乱与阿尔茨海默病的关联及治疗干预
- DOI:
10.1016/j.apsb.2025.04.011 - 发表时间:
2025-06-01 - 期刊:
- 影响因子:14.600
- 作者:
Kishore Madamanchi;Jianhua Zhang;Girish C. Melkani - 通讯作者:
Girish C. Melkani
Exploration and Suppression of Cardiac Amyloidosis Induced by Huntington's Disease-Causing Amyloid in the Drosophila Heart Model
- DOI:
10.1016/j.bpj.2011.11.1923 - 发表时间:
2012-01-31 - 期刊:
- 影响因子:
- 作者:
Girish C. Melkani;Rolf Bodmer;Karen Ocorr;Sanford I. Bernstein - 通讯作者:
Sanford I. Bernstein
The E706K IBM3 Myosin Mutation Depresses the Chemomechanical Properties and Increases the Lability of the Molecular Motor
- DOI:
10.1016/j.bpj.2010.12.909 - 发表时间:
2011-02-02 - 期刊:
- 影响因子:
- 作者:
Anthony Cammarato;Yang Wang;Anju Melkani;Girish C. Melkani;Adam Bialobrodski;Jennifer A. Suggs;William A. Kronert;Sanford I. Bernstein - 通讯作者:
Sanford I. Bernstein
Kinetic Characterization of Converter and Relay Loop Domain Interaction in Drosophila Myosin Sub-Fragment 1
- DOI:
10.1016/j.bpj.2011.11.812 - 发表时间:
2012-01-31 - 期刊:
- 影响因子:
- 作者:
Marieke J. Bloemink;Girish C. Melkani;Michael A. Geeves;Sanford I. Bernstein - 通讯作者:
Sanford I. Bernstein
Girish C. Melkani的其他文献
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{{ truncateString('Girish C. Melkani', 18)}}的其他基金
Promoting circadian rhythms to optimize gut-to-brain signaling for Alzheimer's disease
促进昼夜节律,优化阿尔茨海默病的肠道到大脑信号传导
- 批准号:
10717948 - 财政年份:2023
- 资助金额:
$ 74.98万 - 项目类别:
Dissecting Causal Role of Insomnia in Cardiovascular Disease
剖析失眠与心血管疾病的因果关系
- 批准号:
10455830 - 财政年份:2020
- 资助金额:
$ 74.98万 - 项目类别:
Optimized Circadian Rhythms for the Prevention of Alzheimer's Disease
优化昼夜节律以预防阿尔茨海默病
- 批准号:
10037591 - 财政年份:2020
- 资助金额:
$ 74.98万 - 项目类别:
Molecular basis of circadian rhythms disruptions linked cardiometabolic disorders and their mitigation using dietary intervention
昼夜节律紊乱的分子基础与心脏代谢紊乱及其通过饮食干预的缓解
- 批准号:
10442441 - 财政年份:2020
- 资助金额:
$ 74.98万 - 项目类别:
Dissecting Causal Role of Insomnia in Cardiovascular Disease
剖析失眠与心血管疾病的因果关系
- 批准号:
9974174 - 财政年份:2020
- 资助金额:
$ 74.98万 - 项目类别:
Dissecting Causal Role of Insomnia in Cardiovascular Disease
剖析失眠与心血管疾病的因果关系
- 批准号:
10159305 - 财政年份:2020
- 资助金额:
$ 74.98万 - 项目类别:
Molecular basis of circadian rhythms disruptions linked cardiometabolic disorders and their mitigation using dietary intervention
昼夜节律紊乱的分子基础与心脏代谢紊乱及其通过饮食干预的缓解
- 批准号:
10180848 - 财政年份:2020
- 资助金额:
$ 74.98万 - 项目类别:
Molecular basis of circadian rhythms disruptions linked cardiometabolic disorders and their mitigation using dietary intervention
昼夜节律紊乱的分子基础与心脏代谢紊乱及其通过饮食干预的缓解
- 批准号:
10307949 - 财政年份:2020
- 资助金额:
$ 74.98万 - 项目类别:
Molecular basis of circadian rhythms disruptions linked cardiometabolic disorders and their mitigation using dietary intervention
昼夜节律紊乱的分子基础与心脏代谢紊乱及其通过饮食干预的缓解
- 批准号:
10656450 - 财政年份:2020
- 资助金额:
$ 74.98万 - 项目类别:
Dissecting Causal Role of Insomnia in Cardiovascular Disease
剖析失眠与心血管疾病的因果关系
- 批准号:
10399555 - 财政年份:2020
- 资助金额:
$ 74.98万 - 项目类别:
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