YAP1, neointima formation, and blood pressure regulation

YAP1、新内膜形成和血压调节

基本信息

批准号：
10229472
负责人：
Islam Osman
金额：
$ 12.29万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-05 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229472
关键词：
Acetates Actins Angioplasty Angiotensin II Animal Model Antihypertensive Agents Arterial Injury Atherosclerosis Attenuated Biological Assay Blood Pressure Blood Vessels Cardiovascular Diseases Cause of Death Cell Culture Techniques Collaborations Data Deoxycorticosterone Disease Etiology Exhibits Genes Genetic Transcription Goals Hypertension Impairment In Vitro Infusion procedures Injury Knockout Mice Luciferases Measures Mediating Muscle Contraction PRKCA gene Pharmacology Phase Phenotype Platelet-Derived Growth Factor Platelet-Derived Growth Factor beta Receptor Prevention Proteins Regulatory Pathway Reporter Research Resistance Role Signal Transduction Single Nucleotide Polymorphism Smooth Muscle Smooth Muscle Myocytes Sodium Chloride Structure Telemetry Testing Training Transgenic Animals United States Vascular Diseases Vascular Smooth Muscle Vascular remodeling Vascular resistance Vasoconstrictor Agents base beta Actin blood pressure reduction blood pressure regulation career genome wide association study genomic locus in vivo indexing inhibitor/antagonist insight loss of function mouse model neointima formation novel novel therapeutic intervention polymerization receptor response restenosis transcription factor translational approach vascular smooth muscle cell proliferation

项目摘要

PROJECT SUMMARY Vascular smooth muscle cell (VSMC) phenotypic modulation is central to the etiologies of multiple vascular wall diseases. In post-angioplasty restenosis and atherosclerosis, VSMCs acquire a proliferative/migratory phenotype leading to neointima formation. In contrast, hypertension is largely caused by increased vascular resistance that is attributed to exaggerated VSMC contraction and vascular remodeling. Identification of the key players that regulate VSMC proliferation and contraction is critical for further understanding of the underlying mechanisms of VSMC-driven vascular wall diseases and also for developing novel therapeutic approaches. We have previously demonstrated that the transcription co-factor yes-associated protein 1 (YAP1) promotes VSMC proliferation. Yet, the role and underlying mechanisms of YAP1 in neointima formation in vivo remain unclear. Furthermore, recent genome-wide association studies (GWAS) have identified a loss-of-function single nucleotide polymorphism (SNP) in YAP1 gene locus that was unexpectedly associated with lower blood pressure, suggesting a novel role of YAP1 in blood pressure regulation. The overarching goal of this proposal is to determine the role of YAP1 in regulating both VSMC proliferation and contraction/hypertension. Novel preliminary data in this proposal include 1) YAP1 expression is upregulated after arterial injury and correlates with VSMC proliferation in vivo, 2) YAP1, in association with TEA domain transcription factor 1 (TEAD1), induces platelet-derived growth factor receptor beta (PDGFRb), a putative novel YAP1 target gene that regulates VSMC phenotype, 3) SM-specific Yap1 knockout mice exhibit a hypotensive phenotype and an attenuated response to vasoconstrictors in isolated vessels, and 4) silencing YAP1 in VSMCs inhibited protein kinase C alpha (PRKCa) signaling and impaired actin polymerization, which are key for VSMC contraction. Three specific aims are proposed to test the central hypothesis that YAP1 induces VSMC proliferation and contraction to drive neointima formation and hypertension, respectively. K99 Aim 1. Test the hypothesis that YAP1 induces PDGFRb to promote VSMC proliferation and enhance injury-induced neointima formation in vivo. R00 Aim 2. Test the hypothesis that YAP1 activates PRKCa signaling and promotes actin polymerization to enhance VSMC contraction. R00 Aim 3. Test the hypothesis that VSMC-expressed YAP1 underlies experimental hypertension. Completion of the proposed studies will provide novel insights into the mechanisms regulating VSMC phenotypic modulation and blood pressure regulation and will determine if inhibiting YAP1 is an attractive novel therapeutic strategy for ameliorating both occlusive vascular diseases and hypertension. Additional conceptual and experimental training in hypertension-related research during the K99 phase will help the applicant pursue an independent career and transform this proposal into an R01 application during the R00 phase.

项目摘要血管平滑肌细胞（VSMC）表型调节对于多血管壁的病因至关重要疾病。在血管成形术后再狭窄和动脉粥样硬化中，VSMC获得了增生剂/迁移表型导致新内膜形成。相比之下，高血压主要由血管增加引起电阻归因于夸张的VSMC收缩和血管重塑。钥匙的识别调节VSMC增殖和收缩的玩家对于进一步了解基础至关重要 VSMC驱动的血管壁疾病的机制以及开发新型治疗方法的机制。我们以前证明了转录辅助因子相关蛋白1（YAP1）促进了VSMC 增殖。然而，YAP1在体内新内膜形成中的作用和潜在机制尚不清楚。此外，最近全基因组关联研究（GWAS）已经确定了功能丧失的单一 Yap1基因基因座中的核苷酸多态性（SNP）与较低的血液意外相关压力，表明YAP1在血压调节中的新作用。该提议的总体目标是确定YAP1在调节VSMC增殖和收缩/高血压中的作用。小说本提案中的初步数据包括1）yap1表达在伪影损伤后更新并相关与VSMC增殖在体内，2）Yap1，与茶域转录因子1（TEAD1）相关，诱导血小板衍生的生长因子受体β（PDGFRB），一种推定的小说YAP1靶基因，可调节VSMC 表型，3）SM特异性的Yap1敲除小鼠暴露了降压表型和对衰减的反应分离的血管中的血管收缩剂，4）在VSMC中沉默的YAP1抑制蛋白激酶Cα（PRKCA）信号传导和肌动蛋白聚合受损，这是VSMC收缩的关键。三个具体目标是提议检验YAP1诱导VSMC增殖和收缩以驱动Neintima的中心假设分别形成和高血压。 K99目标1。检验YAP1诱导PDGFRB的假设促进VSMC增殖并增强体内损伤诱导的新内膜形成。 R00 AIM 2。测试 YAP1激活PrkCa信号传导并促进肌动蛋白聚合以增强VSMC的假设收缩。 R00 AIM 3。检验以下假设：VSMC表达的YAP1是实验性高血压的基础。拟议研究的完成将提供有关机制法规VSMC表型的新见解调节和血压调节，并将确定抑制YAP1是否是一种吸引人的新型治疗改善闭塞性血管疾病和高血压的策略。其他概念和在K99阶段进行高血压相关研究的实验培训将帮助申请人购买在R00阶段，独立的职业并将该提案转变为R01应用程序。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

YAP1/TEAD1 upregulate platelet-derived growth factor receptor beta to promote vascular smooth muscle cell proliferation and neointima formation.

DOI：
10.1016/j.yjmcc.2021.03.005
发表时间：
2021-07
期刊：
Journal of molecular and cellular cardiology
影响因子：
5
作者：
Osman I;Dong K;Kang X;Yu L;Xu F;Ahmed ASI;He X;Shen J;Hu G;Zhang W;Zhou J
通讯作者：
Zhou J

CARMN Is an Evolutionarily Conserved Smooth Muscle Cell-Specific LncRNA That Maintains Contractile Phenotype by Binding Myocardin.

DOI：
10.1161/circulationaha.121.055949
发表时间：
2021-12-07
期刊：
Circulation
影响因子：
37.8
作者：
Dong K;Shen J;He X;Hu G;Wang L;Osman I;Bunting KM;Dixon-Melvin R;Zheng Z;Xin H;Xiang M;Vazdarjanova A;Fulton DJR;Zhou J
通讯作者：
Zhou J