Transcriptional Regulation by Angiotensin II in Vascular Smooth Muscle Cells
血管紧张素 II 在血管平滑肌细胞中的转录调节
基本信息
- 批准号:9406145
- 负责人:
- 金额:$ 43.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-01-01 至 2020-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAngiotensin IIAntibodiesAortaApolipoprotein EAtherosclerosisAttenuatedBiological AssayBlood VesselsCRISPR/Cas technologyCardiovascular DiseasesCell physiologyCellsChIP-seqChromatinClinicalCodeCommunitiesDataDiseaseEnhancersEnvironmentEpigenetic ProcessEventFunctional disorderFundingGene ExpressionGene TargetingGenesGrowthHealthcareHistonesHormonesHypertensionHypertrophyIn VitroInflammationInflammatoryKnowledgeLeadMediatingMolecularMorbidity - disease rateMusOligonucleotidesOxidative StressPathologicPathologyPatientsPharmaceutical PreparationsPopulationProteinsRNAReactive Oxygen SpeciesRegulationReporterReportingResourcesRoleSamplingSignal TransductionSmall Interfering RNASmooth Muscle MyocytesTechnologyTestingTherapeuticTranscriptional RegulationUntranslated RNAVascular DiseasesVascular Smooth Musclebasecell growthchromatin modificationchromatin remodelingdiabeticgenome editinggenome-widegenomic profileshistone modificationhuman diseasein vivoin vivo Modelinhibitor/antagonistinnovationinsightlocked nucleic acidloss of functionmigrationmortalitymouse modelnovelpromoterreceptortherapeutic targettranscriptome sequencing
项目摘要
Cardiovascular diseases (CVDs) such as atherosclerosis and hypertension are the leading
causes of morbidity and mortality in our community. Furthermore these vascular complications
are accelerated in the diabetic population. Epigenetic mechanisms have been implicated in
several common human diseases, including CVDs, due to the influence of the environment
which can affect epigenetic states. Evidence shows that the hormone Angiotensin II (Ang II) is a
major player in the pathologies of hypertension and atherosclerosis due to its vasoconstrictive,
pro-inflammatory, pro-oxidant, and growth promoting effects in target cells such as vascular
smooth muscle cells (VSMC). During the previous funding period, we reported the first
functional roles for epigenetic chromatin histone modifications and non-coding RNAs in
mediating some of these deleterious actions of Ang II in VSMCs. In addition, our new
preliminary data show that Ang II can regulate specific novel long non-coding RNAs (lncRNAs),
and enhancers in VSMCs that modulate the expression of target genes associated with VSMC
inflammation and dysfunction. Despite these advances, the functions of specific lncRNAs and
their subtle interactions with other epigenetic factors like enhancers to modulate Ang II-induced
gene expression are still not fully understood. Furthermore, the roles of enhancers,
superenhancers and specific lncRNAs in Ang II-mediated VSMC dysfunction and related CVDs
are not known. Our central hypothesis is that dynamic control of key lncRNAs and VSMC-
specific enhancers/superenhancers, as well as epigenetic cross-talk among these factors,
contribute to Ang II-induced VSMC dysfunction associated with CVDs. This will be tested
through 3 Specific Aims. In Specific Aim 1, we will examine the molecular mechanisms of
regulation and functional roles of two novel lncRNAs that we found to be induced by Ang II in
VSMCs. In Specific Aim 2, we will define the roles of Ang II-regulated enhancers and
superenhancers in the expression of Ang II-regulated genes involved in VSMC functions. In
Specific Aim 3, the in vivo expression and functional roles of the two lncRNAs and candidate
enhancers/SEs will be examined in mouse models of Ang II induced vascular dysfunction and
atherosclerosis. This study examines several new concepts and uses innovative platforms along
with functional in vivo models to gain novel insights into VSMC regulatory networks. The results
and can have potentially far reaching clinical and therapeutic implications for CVDs.
心血管疾病(CVD),如动脉粥样硬化和高血压是主要的
发病率和死亡率的原因。此外,这些血管并发症
在糖尿病人群中加速。表观遗传机制已经被牵连在
几种常见的人类疾病,包括心血管疾病,由于环境的影响,
会影响表观遗传状态有证据表明,激素血管紧张素II(Ang II)是一种
由于其血管收缩性,
在靶细胞如血管内皮细胞中的促炎、促氧化和促生长作用
平滑肌细胞(VSMC)。在上一个融资期间,我们报告了第一个
表观遗传染色质组蛋白修饰和非编码RNA在
介导血管紧张素II在血管平滑肌细胞中的某些有害作用。此外,我们的新
初步数据显示,血管紧张素II可以调节特异性的新型长链非编码RNA(lncRNA),
以及VSMC中调节与VSMC相关的靶基因表达的增强子
炎症和功能障碍。尽管有这些进展,特异性lncRNA和
它们与其他表观遗传因子(如增强子)的微妙相互作用,以调节Ang II诱导的
基因表达仍然没有完全理解。此外,增强子的作用,
血管紧张素II介导的VSMC功能障碍和相关心血管疾病中的超增强剂和特异性lncRNA
不知道。我们的中心假设是关键lncRNA和VSMC的动态控制-
特异性增强子/超增强子,以及这些因子之间的表观遗传串扰,
导致血管紧张素II诱导的血管平滑肌细胞功能障碍与心血管疾病。这将受到考验
三个具体目标。在具体目标1中,我们将研究
我们发现两种新的lncRNA在血管紧张素II诱导下的调节和功能作用,
血管平滑肌细胞。在特异性目标2中,我们将定义血管紧张素II调节增强子的作用,
血管紧张素II调节基因表达的超增强剂参与VSMC功能。在
具体目标3,两种lncRNA和候选lncRNA的体内表达和功能作用
将在Ang II诱导的血管功能障碍的小鼠模型中检查增强子/SE,
动脉粥样硬化本研究探讨了几个新的概念,并使用创新的平台,沿着
功能性体内模型,以获得对VSMC调控网络的新见解。结果
并且可能对CVD具有潜在的深远的临床和治疗意义。
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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RAMA NATARAJAN其他文献
RAMA NATARAJAN的其他文献
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{{ truncateString('RAMA NATARAJAN', 18)}}的其他基金
DIABETES PREVENTION / RISK / OMICS / METABOLISM / THERAPY (PROMT) INTERDISCIPLINARY TRAINING
糖尿病预防/风险/组学/代谢/治疗(PROMT)跨学科培训
- 批准号:
10627642 - 财政年份:2023
- 资助金额:
$ 43.25万 - 项目类别:
Epigenetic Markers of Complications and Metabolic Memory in the DCCT/EDIC cohort.
DCCT/EDIC 队列中并发症和代谢记忆的表观遗传标记。
- 批准号:
8970574 - 财政年份:2015
- 资助金额:
$ 43.25万 - 项目类别:
Transcriptional Regulation by Angiotensin II in Vascular Smooth Muscle Cells
血管紧张素 II 在血管平滑肌细胞中的转录调节
- 批准号:
8206457 - 财政年份:2011
- 资助金额:
$ 43.25万 - 项目类别:
Transcriptional Regulation by Angiotensin II in Vascular Smooth Muscle Cells
血管紧张素 II 在血管平滑肌细胞中的转录调节
- 批准号:
8595327 - 财政年份:2011
- 资助金额:
$ 43.25万 - 项目类别:
Transcriptional Regulation by Angiotensin II in Vascular Smooth Muscle Cells
血管紧张素 II 在血管平滑肌细胞中的转录调节
- 批准号:
9262456 - 财政年份:2011
- 资助金额:
$ 43.25万 - 项目类别:
Transcriptional Regulation by Angiotensin II in Vascular Smooth Muscle Cells
血管紧张素 II 在血管平滑肌细胞中的转录调节
- 批准号:
8399013 - 财政年份:2011
- 资助金额:
$ 43.25万 - 项目类别:
Transcriptional Regulation by Angiotensin II in Vascular Smooth Muscle Cells
血管紧张素 II 在血管平滑肌细胞中的转录调节
- 批准号:
8024654 - 财政年份:2011
- 资助金额:
$ 43.25万 - 项目类别:
Inflammatory Gene Regulation in Diabetic Conditions
糖尿病中的炎症基因调控
- 批准号:
8034544 - 财政年份:2010
- 资助金额:
$ 43.25万 - 项目类别:
Transforming growth factor beta1, microRNAs and diabetic nephropathy
转化生长因子β1、microRNA 和糖尿病肾病
- 批准号:
8772669 - 财政年份:2009
- 资助金额:
$ 43.25万 - 项目类别:
Transforming growth factor beta1, MicroRNAs and Diabetic Nephropathy
转化生长因子 beta1、MicroRNA 和糖尿病肾病
- 批准号:
7652597 - 财政年份:2009
- 资助金额:
$ 43.25万 - 项目类别:
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