Coronary artery disease locus 1p32.2 and miR92a-PPAP2B signaling in endothelial mechanobiology

内皮力学生物学中的冠状动脉疾病基因座 1p32.2 和 miR92a-PPAP2B 信号传导

基本信息

批准号：
10171493
负责人：
Yun Fang
金额：
$ 39.9万
依托单位：
UNIVERSITY OF CHICAGO
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：
2017-08-10 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10171493
关键词：
Address Adult Affect Alleles Allelic Imbalance American Apolipoprotein E Arterial Fatty Streak Arteries Artificial nanoparticles Atherosclerosis Binding Biological Assay Biology Blood Vessels Blood flow Cardiovascular Diseases Complementary DNA Coronary Arteriosclerosis Disease Disease susceptibility EMSA Endothelial Cells Endothelium Enhancers Genes Genetic Diseases Genetic Predisposition to Disease Genetic Variation Goals Human In Vitro Inflammation Introns Investigation Lesion Link Mechanics Mediating MicroRNAs Molecular Morbidity - disease rate Mus Myocardial Infarction Pathway interactions Pharmacology Phenotype Phosphatidate Phosphatase Quantitative Trait Loci Regulation Risk Role Signal Transduction Site Stimulus Stroke Testing Tissues Transgenic Mice Vascular Endothelium athero susceptible atherogenesis causal variant chromosome conformation capture genetic approach genome editing genome wide association study human tissue in vivo in vivo evaluation inhibitor/antagonist innovation insight mechanotransduction monolayer mortality mouse model nanoparticle protective allele risk variant selective expression transcription factor

项目摘要

Project Summary Atherosclerotic arterial disease remains the leading cause of morbidity and mortality among Americans. Atherosclerosis preferentially develops in arterial sites such as curvatures and bifurcations, where endothelial cells are activated by local disturbed flow. Recent studies have suggested new genes and previously unsus- pected biology that mechanistically contribute to atherosclerosis; however, the interplay between genetic pre- disposition of atherosclerosis and flow-mediated endothelial functions remains to be elucidated. Genome-wide association studies (GWAS) and subsequent investigations identified PhosPhatidic-Acid- Phosphatase-type-2B (PPAP2B, also known as LPP3 or PLPP3) as a gene at chr 1p32.2 that significantly influences risk of coronary artery disease (CAD). Moreover, reduced endothelial PPAP2B is associated with increased CAD susceptibility. We recently discovered a new mechanism that links disturbed flow to reduction in endothelial PPAP2B through a microRNA-mediated mechano-transduction pathway: disturbed flow activates endothelial miR-92a, which in turn suppresses PPAP2B directly and also indirectly by inhibiting the transcription factor KLF2 that activates PPAP2B; reduced endothelial PPAP2B then leads to increased endothelial inflammation and compromised monolayer integrity. Furthermore, previous studies showed that systemic delivery of miR-92a inhibitor suppressed miR-92a in a wide range of tissues and lessened atherosclerosis in mice. Although these results suggest that flow-sensitive miR92a-PPAP2B pathway contributes to the athero-susceptible endothelial phenotype, the potentially causal relationship between endothelial miR92a-PPAP2B pathway and atherogenesis in vivo remains uncertain. Moreover, the mechanism by which the CAD-associated causal variant in PPAP2B exerts its effect and its potential roles in endothelial mechano-transduction remains unexplored. We have gathered very strong evidence that PPAP2B genetic variation interacts with unidirectional flow in concert to promote endothelial PPAP2B. The overall goal is to elucidate the molecular convergence of CAD genetic predisposition and mechano-transduction mechanisms in the endothelial miR92a-PPAP2B path- way, dysregulation of which is hypothesized to causatively promote atherosclerosis. Our proposed studies ad- dress three questions of fundamental importance: 1) Does the endothelial miR92a-PPAP2B pathway causally regulate atherosclerosis in vivo? We test this in Aim 1 with new mouse models and innovative nanoparticles to selectively modulate endothelial miR92a-PPAP2B signaling. 2) How does the CAD protective allele at rs17114036 influence PPAP2B expression? In Aim 2, we functionally characterize the rs17114036-depedent enhancer in PPAP2B employing complementary in vivo and in vitro genetic approaches. 3) What is the addi- tional role of KLF2 in regulating allele-specific PPAP2B expression? We address the dynamic regulation of this rs17114036-containing enhancer by mechanical and pharmacological stimuli via KLF2 in Aim 3.

项目摘要动脉粥样硬化动脉疾病仍然是美国人发病率和死亡率的主要原因。动脉粥样硬化优先在动脉部位（例如弯曲和分叉）发展细胞被局部干扰流动激活。最近的研究提出了新基因，以前是不详细的从机械上有助于动脉粥样硬化的生物学；但是，遗传前的相互作用动脉粥样硬化和流动介导的内皮功能的处置尚待阐明。全基因组关联研究（GWAS）和随后的研究鉴定磷酸酶-2b（PPAP2B，也称为LPP3或PLPP3）作为Chr 1p32.2的基因影响冠状动脉疾病（CAD）的风险。此外，减少的内皮PPAP2B与 CAD敏感性提高。我们最近发现了一种新机制，将干扰流与还原联系起来在内皮PPAP2B中通过microRNA介导的机械转移途径：流动障碍激活内皮miR-92a，进而直接抑制PPAP2B并间接抑制激活PPAP2B的转录因子KLF2；减少内皮PPAP2B然后导致增加内皮炎症和单层完整性损害。此外，以前的研究表明 miR-92a抑制剂的全身递送抑制了多种组织中的miR-92a，并减少了小鼠动脉粥样硬化。尽管这些结果表明流动敏感的mir92a-ppap2b途径有助于动脉触摸敏感的内皮表型，这可能是可能因果关系内皮miR92A-PPAP2B途径和体内动脉粥样硬化仍然不确定。而且，机制 PPAP2B中与CAD相关的因果变异的作用及其在内皮中的潜在作用机械转移仍未开发。我们收集了非常有力的证据，表明PPAP2B遗传变异与单向相互作用共同流动以促进内皮PPAP2B。总体目标是阐明分子收敛内皮miR92A-PPAP2B途径中的CAD遗传易感性和机械转移机制方式，假设其失调可在因果关系上促进动脉粥样硬化。我们提出的研究广告打扮三个基本重要性的问题：1）内皮mir92a-ppap2b途径有因果关系调节体内动脉粥样硬化？我们在AIM 1中使用新的鼠标模型和创新纳米颗粒对此进行测试选择性调节内皮miR92a-PPAP2B信号传导。 2）CAD保护等位基因如何 RS17114036影响PPAP2B表达？在AIM 2中，我们在功能上表征RS17114036-DEPEDENT PPAP2B中使用互补的体内和体外遗传方法的增强子。 3）什么是 KLF2在调节等位基因特异性PPAP2B表达中的角色？我们解决了这一点的动态调节 AIM 3中通过KLF2通过机械和药理学刺激含有RS17114036的增强子。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting mechanosensitive endothelial TXNDC5 to stabilize eNOS and reduce atherosclerosis in vivo.

DOI：
10.1126/sciadv.abl8096
发表时间：
2022-01-21
期刊：
Science advances
影响因子：
13.6
作者：
Yeh CF;Cheng SH;Lin YS;Shentu TP;Huang RT;Zhu J;Chen YT;Kumar S;Lin MS;Kao HL;Huang PH;Roselló-Sastre E;Garcia F;Jo H;Fang Y;Yang KC
通讯作者：
Yang KC

The Runt of the Litter-Stronger than We Thought?

幼崽中的弱者——比我们想象的更强？