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Switch of Osteogenesis in Vascular Calcification

血管钙化中成骨的转换

基本信息

批准号：
10358948
负责人：
Yucheng Yao
金额：
$ 39万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10358948
关键词：
Activities of Daily Living Affect American Aorta Back CDC2 gene Cell Proliferation Cells Complications of Diabetes Mellitus Cyclin-Dependent Kinase Inhibitor Diabetes Mellitus Diabetic mouse Disease Endothelial Cells Endothelium Genetic Genetic Transcription Investigation Label Lead Maps Mesenchymal Modeling Morbidity - disease rate Mus Osteoblasts Osteogenesis Patients Persons Process Proteins Public Health Resolution Source Specificity Testing Therapeutic Tissues Variant Vascular Diseases Vascular Endothelial Cell Vascular Endothelium Vascular calcification Work bone cell calcification diabetic diabetic patient effective therapy high risk improved inhibitor matrix Gla protein mortality mouse model novel strategies novel therapeutic intervention osteogenic osteoprogenitor cell prevent single-cell RNA sequencing treatment strategy

项目摘要

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.

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。