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.

项目概要血管平滑肌细胞（VSMC）表型调节是多血管壁病因的核心在血管成形术后再狭窄和动脉粥样硬化中，VSMC 获得增殖/迁移。相反，高血压主要是由血管增加引起的。认为归因于VSMC过度收缩和血管重塑的阻力是识别的关键。调节 VSMC 增殖和收缩的参与者对于进一步了解潜在的机制至关重要 VSMC 驱动的血管壁疾病的机制，以及开发新的治疗方法。先前已证明转录辅助因子 yes 相关蛋白 1 (YAP1) 促进 VSMC 然而，YAP1 在体内新内膜形成中的作用和潜在机制仍不清楚。此外，最近的全基因组关联研究（GWAS）发现了一个功能丧失的单基因 YAP1 基因位点的核苷酸多态性 (SNP) 与较低的血液水平出乎意料地相关压力，表明 YAP1 在血压调节中的新作用该提案的首要目标是确定 YAP1 在调节 VSMC 增殖和收缩/高血压中的作用。该提案中的初步数据包括 1) YAP1 表达在动脉损伤后上调并与与 VSMC 体内增殖有关，2) YAP1 与 TEA 域转录因子 1 (TEAD1) 结合，诱导血小板衍生生长因子受体β (PDGFRb)，一种假定的调节 VSMC 的新型 YAP1 靶基因表型，3) SM 特异性 Yap1 敲除小鼠表现出低血压表型和减弱的反应分离血管中的血管收缩剂，4) 沉默 VSMC 中的 YAP1 会抑制蛋白激酶 C α (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。提出检验YAP1诱导VSMC增殖和收缩以驱动新内膜的中心假设 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 目标 2. 测试假设 YAP1 激活 PRKCa 信号传导并促进肌动蛋白聚合以增强 VSMC R00 目标 3. 检验 VSMC 表达的 YAP1 是实验性高血压的基础的假设。完成拟议的研究将为调节 VSMC 表型的机制提供新的见解调节和血压调节，并将确定抑制 YAP1 是否是一种有吸引力的新型疗法改善闭塞性血管疾病和高血压的策略。 K99阶段高血压相关研究的实验培训将帮助申请人追求独立职业生涯，并在 R00 阶段将此提案转化为 R01 申请。

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）

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

CARMN 是一种进化上保守的平滑肌细胞特异性 LncRNA，通过结合心肌素来维持收缩表型。

DOI：
发表时间：
2021-12-07
期刊：
影响因子：
37.8
作者：
Dong, Kunzhe;Shen, Jian;He, Xiangqin;Hu, Guoqing;Wang, Liang;Osman, Islam;Bunting, Kristopher M;Dixon;Zheng, Zeqi;Xin, Hongbo;Xiang, Meixiang;Vazdarjanova, Almira;Fulton, David J R;Zhou, Jiliang
通讯作者：
Zhou, Jiliang

Deficiency of the novel high mobility group protein HMGXB4 protects against systemic inflammation-induced endotoxemia in mice.

新型高迁移率族蛋白 HMGXB4 的缺乏可以保护小鼠免受全身炎症诱导的内毒素血症。

DOI：
发表时间：
2021
期刊：
影响因子：
11.1
作者：
He, Xiangqin;Dong, Kunzhe;Shen, Jian;Hu, Guoqing;Liu, Jinhua;Kang, Xiuhua;Wang, Liang;Atawia, Reem T;Osman, Islam;Caldwell, Robert W;Xiang, Meixiang;Zhang, Wei;Zheng, Zeqi;Li, Liwu;Fulton, David J R;Deng, Keyu;Xin, Hongbo;Zhou, Jiliang
通讯作者：
Zhou, Jiliang

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

YAP1/TEAD1 上调血小板衍生生长因子受体β，促进血管平滑肌细胞增殖和新内膜形成。