Identification of smooth muscle cell genes causal in atherosclerotic plaque stability and cardiovascular disease risk
鉴定导致动脉粥样硬化斑块稳定性和心血管疾病风险的平滑肌细胞基因
基本信息
- 批准号:10720225
- 负责人:
- 金额:$ 69.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-10 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAffectAllelesArterial Fatty StreakArteriesAtherosclerosisBiologicalBiological AssayBloodBlood VesselsCallbackCardiovascular DiseasesCarotid ArteriesCarotid Artery PlaquesCell AgingCell LineageCell ProliferationCellsCholesterolClinicalCoronary ArteriosclerosisDataDiseaseDisease regressionEtiologyFamilyGene DeletionGene ExpressionGenesGeneticGenetic VariationGenome MappingsHeterozygoteHistologyHumanHuman GeneticsHuman ResourcesKnock-outLesionLigationLipidsLipoproteinsLocationLow-Density LipoproteinsMapsMeta-AnalysisMusMutationPakistanParticipantPathway interactionsPhenotypePlasmaPlayPopulation GeneticsRNAResidual stateResolutionResourcesRoleSafetySignal TransductionSmooth Muscle MyocytesStable DiseaseSystemTestingTimeTretinoinVariantVascular Smooth MuscleVascular remodelingWorkbiobankcardiovascular disorder riskcausal variantcell typecohortconditional knockoutcoronary artery calciumexomefine artgene functiongenetic analysisgenetic pedigreegenome resourcegenome sequencinggenome wide association studyhuman modelimprovedin situ sequencingintimal medial thickeningknockout geneloss of functionmouse modelmulti-ethnicpleiotropismprogramsrare variantrecombinasesafety assessmentsenescencesingle-cell RNA sequencingtherapeutic targettraittranscriptome sequencingtranscriptomic profilingtranscriptomicswhole genome
项目摘要
Despite effective LDL-C therapies, cardiovascular disease (CVD) risk remains a major unmet clinical need. We
and others have identified >300 loci for coronary artery disease (CAD). Genes that function in vascular smooth
muscle cells (SMC) are causal at several loci yet the causal genes at most loci remain unknown. Using single
cell profiling and SMC lineage-tracing in mouse models, we found that SMC transition through an intermediate
SMC-derived cell (SDC) state into protective or harmful phenotypes that modulate disease. We hypothesize that
SMC genes play a prominent causal role in plaque instability and CVD risk independent of lipoprotein genes. To
address this, we will leverage unique mouse model and human resources, including the Pakistan Genomics
Resource (PGR, n=250,000 for study) that includes the largest global cohort of human gene knockout “KOs”
(complete KOs >5000; heterozygous KOs >18,000 genes) as well as the Munich Vascular Biobank (MVB) with
>2,000 human plaques and clinical, histology, transcriptomics and genetic data. In Aim 1, we will integrate SMC
lineage tracing in mouse models with analyses of >1 million participants with GWAS SNP, whole-exome (WES)
and whole-genome (WGS) data, eliminating all loci/genes associated with plasma lipoproteins. Implementing
the largest rare variant and gene burden testing for CAD to date, we will prioritize likely causal SMC/SDC genes
and reveal predicted loss of function (pLoF) variant directional effects. To operationalize call-back studies, we
will limit to genes with at least 5 pLoF carriers in PGR. Gene priority will be refined by multiethnic fine-mapping,
co-localization analyses and biological plausibility. We expect to prioritize ~30 SMC/SDC genes. All will undergo
large PheWAS for pleiotropy and safety. For the top 5 genes, call-back studies will validate causality and
directionality and assess safety through deep phenotyping of atherosclerosis traits, safety and pleiotropy markers
in PGR families (n=200 per family). Preliminary work prioritized 15 SMC/SDC genes, all strong causal
candidates, and initial call-back in PGR expanded large pedigrees for the most promising genes (e.g., PDE3A,
SERPINH1, HHIPL1, ZEB2). In Aim 2, we will use RNA in situ sequencing (HybRISS), RNA-scope, proximity
ligation assays (Myh11-H3K4me2 SMC/SDC mark) and histology to define SMC/SDC gene expression and
location for ~30 prioritized genes in stable vs. unstable MVB plaques. Change in allele specific expression for
genes in SDC types in stable vs. unstable MVB plaques and co-localization of their cis-eQTLs to CAD SNPs will
inform causal and directional effects on plaque stability. For at least 2 top genes, we will use a Tet-on Dre/Cre
dual inducible recombinase system for SMC gene deletion at late time points to test effects and mechanisms on
features of plaque stability in advanced lesions and disease regression. We are poised to test in mouse models
if PDE3A, one compelling example, promotes SMC proliferation, senescence and vascular remodeling. Overall,
we propose a unique integrative platform, validated by human genetics, to fine-map loci, discover causal genes
and elucidate safe therapeutic targets in SMC/SDCs causal pathways for atherosclerosis stability and CVD risk.
尽管有有效的低密度脂蛋白-C疗法,心血管疾病(CVD)的风险仍然是一个主要的未得到满足的临床需求。我们
其他人已经确定了冠状动脉疾病(CAD)的>;300个基因座。在血管顺畅中起作用的基因
肌肉细胞(SMC)在几个基因座上是因果的,但大多数基因座上的因果基因仍不清楚。使用Single
在小鼠模型中,我们发现SMC通过一种中间体
SMC来源的细胞(SDC)进入保护性或有害的表型,从而调节疾病。我们假设
SMC基因在斑块不稳定性和心血管疾病风险中起重要作用,而不依赖于脂蛋白基因。至
为了解决这个问题,我们将利用独特的老鼠模型和人力资源,包括巴基斯坦基因组公司
资源(PGR,n=250,000用于研究),包括全球最大的人类基因敲除“KO”队列
(完整的KOS和GT;5000个;杂合的KOS和GT;18,000个基因)以及慕尼黑血管生物库(MVB)
>;2,000个人类斑块以及临床、组织学、转录学和基因数据。在目标1中,我们将集成SMC
小鼠模型的谱系追踪--分析100万名GWASSNP,WES全外显子(WES)受试者
和全基因组(WGS)数据,消除与血浆脂蛋白相关的所有基因座/基因。实施
这是迄今为止最大的CAD罕见变异和基因负荷测试,我们将优先考虑可能导致SMC/SDC的基因
并揭示了预测功能丧失(PLoF)的不同定向效应。为落实回拨研究,我们
将限于PGR中至少有5个pLoF携带者的基因。基因优先级将通过多种族精细图谱进行细化,
共同定位分析和生物学上的合理性。我们预计将优先处理约30个SMC/SDC基因。所有人都会经历
用于多效性和安全性的大型苯系物。对于排名前5位的基因,回拨研究将验证因果关系和
通过动脉粥样硬化特征、安全性和多效性标志物的深层表型进行方向性和安全性评估
在PGR家系中(每个家庭200人)。初步工作确定了15个SMC/SDC基因的优先顺序,所有这些基因都具有很强的因果关系
候选基因和在PGR中的初始回调扩大了最有希望的基因的大型家系(例如,PDE3A,
SERPINH1、HHIPL1、ZEB2)。在目标2中,我们将使用RNA原位测序(HybRISS)、RNA-SCOPE、邻近
连接分析(MYH11-H3K4me2 SMC/SDC标记)和组织学以确定SMC/SDC基因的表达和
稳定与不稳定MVB斑块中约30个优先基因的位置。等位基因特异性表达的变化
稳定和不稳定MVB斑块中SDC类型的基因及其顺式eQTL与CAD SNPs的共定位将
告知斑块稳定性的因果和方向性影响。对于至少两个顶级基因,我们将使用Tet-on DRE/Cre
双诱导型重组酶系统检测SMC基因晚期缺失的作用及机制
晚期病变斑块稳定性和疾病消退的特点。我们准备在老鼠模型上进行测试
PDE3A就是一个引人注目的例子,它促进了SMC的增殖、衰老和血管重构。总的来说,
我们提出了一个独特的整合平台,经过人类遗传学的验证,用于精细定位基因座,发现因果基因
阐明SMC/SDCs致病途径中动脉粥样硬化稳定性和心血管风险的安全治疗靶点。
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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Muredach P Reilly其他文献
Single-cell multimodal profiling of monocytes reveals diverse phenotypes and alterations linked to cardiovascular disease risks
单核细胞的单细胞多模式分析揭示了与心血管疾病风险相关的多种表型和变化
- DOI:
10.1101/2024.02.18.580913 - 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Alexander C. Bashore;Chenyi Xue;Eunyoung Kim;Hanying Yan;Lucie Y. Zhu;Huize Pan;Michael D Kissner;Leila S Ross;Hanrui Zhang;Mingyao Li;Muredach P Reilly - 通讯作者:
Muredach P Reilly
1008-184 The effects of pravastatin and atorvastatin on markers of oxidant stress in vivo
- DOI:
10.1016/s0735-1097(04)91877-3 - 发表时间:
2004-03-03 - 期刊:
- 影响因子:
- 作者:
Bonnie Ky;Megan L Wolfe;Anne Burke;Philippe O Szapary;Muredach P Reilly;Jennifer B Dykhouse;Leanne T Bloedon;Garret A FitzGerald;Daniel J Rader - 通讯作者:
Daniel J Rader
Muredach P Reilly的其他文献
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{{ truncateString('Muredach P Reilly', 18)}}的其他基金
Smooth muscle cell-derived cell fates and cellular interactions in atherosclerotic plaque stability in disease progression and regression.
平滑肌细胞衍生的细胞命运和细胞相互作用在疾病进展和消退中动脉粥样硬化斑块的稳定性。
- 批准号:
10567844 - 财政年份:2023
- 资助金额:
$ 69.24万 - 项目类别:
Human LincRNAs in Macrophage Biology and Related Cardiometabolic Diseases
巨噬细胞生物学和相关心脏代谢疾病中的人类 LincRNA
- 批准号:
9402855 - 财政年份:2017
- 资助金额:
$ 69.24万 - 项目类别:
Human LincRNAs in Macrophage Biology and Related Cardiometabolic Diseases
巨噬细胞生物学和相关心脏代谢疾病中的人类 LincRNA
- 批准号:
9983136 - 财政年份:2017
- 资助金额:
$ 69.24万 - 项目类别:
Human LincRNAs in Macrophage Biology and Related Cardiometabolic Diseases
巨噬细胞生物学和相关心脏代谢疾病中的人类 LincRNA
- 批准号:
9531432 - 财政年份:2017
- 资助金额:
$ 69.24万 - 项目类别:
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