The Role of Endothelial Cell Mineralocorticoid Receptors in the Development of Vascular Inflammation and Atherosclerosis
内皮细胞盐皮质激素受体在血管炎症和动脉粥样硬化发展中的作用
基本信息
- 批准号:9326395
- 负责人:
- 金额:$ 3.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-10 至 2021-06-09
- 项目状态:已结题
- 来源:
- 关键词:ActinsAdhesionsAldosteroneAmericanAnimalsArterial Fatty StreakArteriesAtherosclerosisAutoimmune DiseasesAutomobile DrivingBindingBlood VesselsCardiovascular DiseasesCardiovascular systemCaringCause of DeathCell Culture TechniquesCellsCholesterolChronicClinicalClinical ResearchCollaborationsCultured CellsDangerousnessDataDevelopmentDyslipidemiasEndothelial CellsEndotheliumEventExtravasationFibrosisFlow CytometryFoundationsFunctional disorderHealthHeart failureHigh Fat DietHistologicHumanHyperlipidemiaHypertensionImmunologyIn VitroInfiltrationInflammationInflammatoryInfusion proceduresInjectableIntercellular JunctionsInvestigationIschemiaIschemic StrokeKnock-outLeadLeukocytesLightLimb structureLipidsMeasuresMediatingMethodsMineralocorticoid ReceptorMitogen-Activated Protein KinasesModelingMorbidity - disease rateMorphologyMusMyocardial InfarctionNecrosisNeoplasm MetastasisObesityOxidesPathologyPathway interactionsPermeabilityPhenotypePhospholipidsPhysiciansPlant RootsPlasma ProteinsPreventionProcessPublishingRandomized Clinical TrialsReceptor ActivationReceptor CellReceptor InhibitionRecruitment ActivityResearchRiskRisk FactorsRoleRuptureScientistSignal PathwaySignal TransductionStress FibersStrokeT-LymphocyteTestingThrombosisTrainingVascular DiseasesVeinsViral VectorWorkadeno-associated viral vectoraortic archatherogenesiscadherin 5cardiovascular risk factorcareerclinically significantendothelial dysfunctionin vivointravital microscopyjunctional adhesion moleculemacrophagemeetingsmigrationmonolayermortalitymouse modelmutantnovelnovel therapeuticsoccludinoverexpressionpreventresponsetraining opportunityvascular endothelial dysfunctionvascular inflammation
项目摘要
Project Summary/Abstract
Cardiovascular disease is the most common cause of death in the USA, mainly due to rupture of
atherosclerotic plaques causing myocardial infarction (MI) and stroke. Excess activation of the
mineralocorticoid receptor (MR) is associated with vascular inflammation, atherosclerotic plaque rupture, and
increased risk of MI and stroke. As MR activation is associated with obesity, heart failure, and hypertension, all
very common health conditions, the majority of Americans may be at increased risk for MI and stroke due to
inappropriate MR activation. Prior research in our lab and others indicates that MR in the vasculature promotes
vascular inflammation and atherosclerosis, while its inhibition results in smaller plaques and fewer adverse
cardiovascular events in randomized clinical trials. In response to traditional cardiovascular risk factors such as
hypertension, obesity, and, we have recently found, hyperlipidemia, the MR specifically within endothelial cells
(EC-MR) mediates vascular dysfunction, which is widely known to be an early step in the formation of
atherosclerotic plaques. We have also found that EC-MR promotes leukocyte adhesion and trans-endothelial
migration, suggesting a mechanism for how the MR promotes vascular inflammation. We therefore
hypothesize that hyperlipidemia induces EC-MR to maladaptively activate intracellular pathways that promote
endothelial permeability, thereby facilitating leukocyte trans-endothelial migration and vascular inflammation
and contributing to development of atherosclerotic plaques with a phenotype that is prone to rupture. To
investigate this hypothesis, we have developed a novel mouse model with the MR specifically deleted from
endothelial cells, which we inject with a viral vector containing constitutively active PCSK9 to induce
hyperlipidemia and atherosclerosis. In aim 1 of this proposal, we will investigate the role of EC-MR in plaque
formation and morphology, vascular inflammation, and leukocyte trans-endothelial migration in vivo using this
mouse model. In aim 2, we will treat isolated endothelial cells in culture with oxidized phospholipids to model
atherogenic conditions and investigate intracellular signaling, cell-cell junction stability, and leukocyte trans-
endothelial migration in vitro. Successful completion of our aims will result in substantial advances in our
understanding of atherosclerosis and inflammation and could lead to novel therapies specifically targeting EC-
MR to reduce atherosclerotic plaque burden and plaque rupture, drastically reducing the morbidity and
mortality from cardiovascular disease. This proposal also includes a detailed training plan including
coursework, collaborations, presentations at national meetings, and integration of clinical training to prepare
the PI for a successful career as a physician-scientist.
项目总结/摘要
心血管疾病是美国最常见的死亡原因,主要是由于心血管系统破裂。
动脉粥样硬化斑块导致心肌梗塞(MI)和中风。过度激活
盐皮质激素受体(MR)与血管炎症、动脉粥样硬化斑块破裂和
增加MI和中风的风险。由于MR激活与肥胖、心力衰竭和高血压相关,所有
非常常见的健康状况,大多数美国人可能会增加MI和中风的风险,
不适当的MR激活。我们实验室和其他实验室的先前研究表明,脉管系统中的MR促进了
血管炎症和动脉粥样硬化,而它的抑制导致更小的斑块和更少的不良反应。
随机临床试验中的心血管事件。针对传统的心血管风险因素,如
高血压,肥胖,以及我们最近发现的高脂血症,MR特别是在内皮细胞内
(EC-MR)介导血管功能障碍,这是众所周知的形成的早期步骤,
动脉粥样硬化斑块。我们还发现,EC-MR促进白细胞粘附和跨内皮细胞粘附。
迁移,表明MR如何促进血管炎症的机制。因此我们
假设高脂血症诱导EC-MR不适应地激活细胞内途径,
内皮通透性,从而促进白细胞跨内皮迁移和血管炎症
并且有助于具有易于破裂的表型的动脉粥样硬化斑块的发展。到
为了研究这一假设,我们开发了一种新的小鼠模型,其中MR特异性地从
内皮细胞,我们注射含有组成型活性PCSK 9的病毒载体,以诱导
高脂血症和动脉粥样硬化。在本提案的目标1中,我们将研究EC-MR在斑块中的作用,
形成和形态,血管炎症,和白细胞跨内皮迁移在体内使用这个
小鼠模型在目标2中,我们将用氧化磷脂处理培养的分离的内皮细胞,
动脉粥样硬化的条件,并研究细胞内信号,细胞-细胞连接的稳定性,和白细胞跨膜。
体外内皮迁移。成功地完成我们的目标将导致我们的实质性进展,
了解动脉粥样硬化和炎症,并可能导致专门针对EC的新疗法,
MR减少动脉粥样硬化斑块负荷和斑块破裂,大幅降低发病率,
心血管疾病的死亡率。该提案还包括一份详细的培训计划,
课程,合作,在国家会议上的演讲,以及临床培训的整合,以准备
作为一名成功的医学科学家的PI。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Mary Elizabeth Moss其他文献
Mary Elizabeth Moss的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Mary Elizabeth Moss', 18)}}的其他基金
The Role of Endothelial Cell Mineralocorticoid Receptors in the Development of Vascular Inflammation and Atherosclerosis
内皮细胞盐皮质激素受体在血管炎症和动脉粥样硬化发展中的作用
- 批准号:
9908157 - 财政年份:2017
- 资助金额:
$ 3.98万 - 项目类别:
相似海外基金
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
- 批准号:
BB/Y004841/1 - 财政年份:2024
- 资助金额:
$ 3.98万 - 项目类别:
Research Grant
Defining a role for non-canonical mTORC1 activity at focal adhesions
定义非典型 mTORC1 活性在粘着斑中的作用
- 批准号:
BB/Y001427/1 - 财政年份:2024
- 资助金额:
$ 3.98万 - 项目类别:
Research Grant
How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.
张力蛋白如何将粘着斑转化为纤维状粘连并相分离以形成新的粘连信号中枢。
- 批准号:
BB/Y005414/1 - 财政年份:2024
- 资助金额:
$ 3.98万 - 项目类别:
Research Grant
Development of a single-use, ready-to-use, sterile, dual chamber, dual syringe sprayable hydrogel to prevent postsurgical cardiac adhesions.
开发一次性、即用型、无菌、双室、双注射器可喷雾水凝胶,以防止术后心脏粘连。
- 批准号:
10669829 - 财政年份:2023
- 资助金额:
$ 3.98万 - 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
- 批准号:
10587090 - 财政年份:2023
- 资助金额:
$ 3.98万 - 项目类别:
Improving Maternal Outcomes of Cesarean Delivery with the Prevention of Postoperative Adhesions
通过预防术后粘连改善剖宫产的产妇结局
- 批准号:
10821599 - 财政年份:2023
- 资助金额:
$ 3.98万 - 项目类别:
Regulating axon guidance through local translation at adhesions
通过粘连处的局部翻译调节轴突引导
- 批准号:
10841832 - 财政年份:2023
- 资助金额:
$ 3.98万 - 项目类别:
Prevention of Intraabdominal Adhesions via Release of Novel Anti-Inflammatory from Surface Eroding Polymer Solid Barrier
通过从表面侵蚀聚合物固体屏障中释放新型抗炎剂来预防腹内粘连
- 批准号:
10532480 - 财政年份:2022
- 资助金额:
$ 3.98万 - 项目类别:
I-Corps: A Sprayable Tissue-Binding Hydrogel to Prevent Postsurgical Cardiac Adhesions
I-Corps:一种可喷雾的组织结合水凝胶,可防止术后心脏粘连
- 批准号:
10741261 - 财政年份:2022
- 资助金额:
$ 3.98万 - 项目类别:
Sprayable Polymer Blends for Prevention of Site Specific Surgical Adhesions
用于预防特定部位手术粘连的可喷涂聚合物共混物
- 批准号:
10674894 - 财政年份:2022
- 资助金额:
$ 3.98万 - 项目类别: