Switch of Osteogenesis in Vascular Calcification
Switch of Osteogenesis in Vascular Calcification
批准号:
10358948
负责人:
Yucheng Yao
金额:
$39.0万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
未结题
起止时间:
2018-07-01 至 2026-06-30
关键词:
Activities of Daily LivingAffectAmericanAortaBackCDC2 geneCell ProliferationCellsComplications of Diabetes MellitusCyclin-Dependent Kinase InhibitorDiabetes MellitusDiabetic mouseDiseaseEndothelial CellsEndotheliumGeneticGenetic TranscriptionInvestigationLabelLeadMapsMesenchymalModelingMorbidity - disease rateMusOsteoblastsOsteogenesisPatientsPersonsProcessProteinsPublic HealthResolutionSourceSpecificityTestingTherapeuticTissuesVariantVascular DiseasesVascular Endothelial CellVascular EndotheliumVascular calcificationWorkbone cellcalcificationdiabeticdiabetic patienteffective therapyhigh riskimprovedinhibitormatrix Gla proteinmortalitymouse modelnovel strategiesnovel therapeutic interventionosteogenicosteoprogenitor cellpreventsingle-cell RNA sequencingtreatment strategy
中文摘要
总结
血管钙化的治疗进展可能具有深远的公共利益。血管钙化是
糖尿病并发症多,发病率和死亡率增加。虽然
确切的机制尚未确定,血管钙化是一个活跃的过程
涉及异位骨形成,其中成骨分化发生在从骨形成细胞转分化的细胞中。
其他血统。以往的研究表明,血管内皮细胞(ECs)的开关细胞命运分化
成骨细胞样细胞来促进血管钙化。然而,目前尚不清楚是否将
EC衍生的成骨细胞样细胞恢复内皮分化的转录景观改善
血管钙化在目前的提议中,我们利用单细胞RNA测序(scRNA-seq),
连接图(CMap),以确定一种新的方法,旨在改变EC衍生的转录景观
成骨样细胞向内皮细胞分化,并探讨其对糖尿病血管钙化的影响
糖尿病。在初步研究中,我们使用谱系追踪、scRNA-seq和CMap查询来鉴定细胞周期蛋白依赖性
激酶1(CDK 1)抑制以将EC衍生的成骨细胞样细胞重定向至内皮分化,
显著改善血管钙化。我们发现在EC衍生的成骨细胞样细胞中特异性诱导CDK 1,
细胞我们发现,CDK 1缺失或其抑制剂AT 7519增加了E-26特异性序列变体2,
(ETV 2),其负责将EC衍生的成骨细胞样细胞的转录景观转移到
内皮分化此外,EC或AT 7519中的CDK 1缺失减少了EC衍生的骨生成,
降低糖尿病Ins 2 Akita/+小鼠的主动脉钙化,而不影响其他组织。因此,我们假设
CDK 1抑制诱导ETV 2将EC衍生的成骨细胞样细胞重新定向为内皮分化,
进而改善糖尿病中血管钙化。在具体目标1中,我们将阐明其机制
潜在的CDK 1抑制,使EC衍生的成骨细胞样细胞向内皮分化。在
具体目标2,我们将确定CDK 1抑制是否改善糖尿病小鼠模型中的血管钙化。
如果成功,它将建立一个新的概念,将命运多舛的细胞重新定向到正常化,
抑制可能成为治疗获得性血管疾病中钙化的一种新的治疗方法。
英文摘要
SUMMARY
Therapeutic advances in vascular calcification may have far-reaching public benefits. Vascular calcification is a
frequent complication of diabetes mellitus and associated with the increase of morbidity and mortality. Although
the precise mechanism has not been determined, vascular calcification is known to be an active process
involving ectopic bone formation, in which osteogenic differentiation occurs in the cells transdifferentiated from
other lineages. Previous studies have shown that vascular endothelial cells (ECs) switch cell fate to differentiate
into osteoblastic-like cells to contribute to vascular calcification. However, it is unknown if shifting the
transcriptional landscape of EC-derived osteoblast-like cells back to endothelial differentiation ameliorates
vascular calcification. In present proposal, we take advantage of single-cell RNA sequencing (scRNA-seq) and
connectivity Map (CMap) to identify a novel approach, aiming to shift the transcriptional landscape of EC-derived
osteoblast-like cells to endothelial differentiation and investigate its effect on vascular calcification in diabetes
mellitus. In preliminary study, we use lineage tracing, scRNA-seq and CMap query to identify cyclin-dependent
kinase 1 (CDK1) inhibition to redirect EC-derived osteoblast-like cells to endothelial differentiation and
significantly improve vascular calcification. We find a specific induction of CDK1 in EC-derived osteoblast-like
cells. We show that CDK1 deletion or its inhibitor AT7519 increases E-twenty-six specific sequence variant 2
(ETV2), which is responsible for shifting the transcriptional landscape of EC-derived osteoblast-like cells to
endothelial differentiation. Furthermore, CDK1 deletion in ECs or AT7519 reduces EC-derived osteogenesis and
decreases aortic calcification in diabetic Ins2Akita/+ mice without affecting other tissues. Therefore, we hypothesize
that CDK1 inhibition induces ETV2 to redirect EC-derived osteoblast-like cells back to endothelial differentiation
in turn to ameliorate vascular calcification in diabetes mellitus. In specific Aim 1, we will elucidate the mechanism
underlying CDK1 inhibition that shifts EC-derived osteoblast-like cells toward endothelial differentiation. In
specific Aim 2, we will determine if CDK1 inhibition ameliorates vascular calcification in a diabetic mouse model.
If successful, it will build the redirection of ill-fated cells back to normalization as a new concept, and the CDK1
inhibition may emerge as a new therapeutic approach to treat calcification in acquired vascular diseases.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Erasing ill features of arterial endothelial cells in hereditary hemorrhagic telangiectasia
-
批准号:10413737
-
项目类别:
-
资助金额:$39.0万
-
财政年份:2022
-
负责人:Yucheng Yao
-
依托单位:
Erasing ill features of arterial endothelial cells in hereditary hemorrhagic telangiectasia
-
批准号:10586071
-
项目类别:
-
资助金额:$39.0万
-
财政年份:2022
-
负责人:Yucheng Yao
-
依托单位:
Switch of Osteogenesis in Vascular Calcification
-
批准号:10197203
-
项目类别:
-
资助金额:$39.0万
-
财政年份:2018
-
负责人:Yucheng Yao
-
依托单位:
Switch of Osteogenesis in Vascular Calcification
-
批准号:10625984
-
项目类别:
-
资助金额:$39.0万
-
财政年份:2018
-
负责人:Yucheng Yao
-
依托单位:
BMP and Notch Crosstalk in Cerebral Arteriovenous Malformations
-
批准号:8845268
-
项目类别:
-
资助金额:$33.69万
-
财政年份:2012
-
负责人:Yucheng Yao
-
依托单位:
BMP and Notch crosstalk in cerebral arteriovenous malformations
-
批准号:9381141
-
项目类别:
-
资助金额:$33.69万
-
财政年份:2012
-
负责人:Yucheng Yao
-
依托单位:
BMP and Notch crosstalk in cerebral arteriovenous malformations
-
批准号:10518011
-
项目类别:
-
资助金额:$39.0万
-
财政年份:2012
-
负责人:Yucheng Yao
-
依托单位:
BMP and Notch crosstalk in cerebral arteriovenous malformations
-
批准号:9927680
-
项目类别:
-
资助金额:$33.69万
-
财政年份:2012
-
负责人:Yucheng Yao
-
依托单位:
BMP and Notch Crosstalk in Cerebral Arteriovenous Malformations
-
批准号:8473295
-
项目类别:
-
资助金额:$32.51万
-
财政年份:2012
-
负责人:Yucheng Yao
-
依托单位:
BMP and Notch Crosstalk in Cerebral Arteriovenous Malformations
-
批准号:8666677
-
项目类别:
-
资助金额:$33.35万
-
财政年份:2012
-
负责人:Yucheng Yao
-
依托单位:
BMP and Notch crosstalk in cerebral arteriovenous malformations
-
批准号:10626951
-
项目类别:
-
资助金额:$39.0万
-
财政年份:2012
-
负责人:Yucheng Yao
-
依托单位:
BMP and Notch Crosstalk in Cerebral Arteriovenous Malformations
-
批准号:8340898
-
项目类别:
-
资助金额:$33.69万
-
财政年份:2012
-
负责人:Yucheng Yao
-
依托单位:
BMP and Notch crosstalk in cerebral arteriovenous malformations
-
批准号:10171922
-
项目类别:
-
资助金额:$33.69万
-
财政年份:2012
-
负责人:Yucheng Yao
-
依托单位:
海外基金