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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性疾病仍然是美国人发病率和死亡率的主要原因。动脉粥样硬化优先发生在动脉部位，如弯曲和分叉，其中内皮细胞细胞被局部扰动流激活。最近的研究表明，新的基因和以前不一致的- 预期的生物学机制有助于动脉粥样硬化;然而，遗传前，动脉粥样硬化的分布和血流介导的内皮功能仍有待阐明。全基因组关联研究（GWAS）和随后的调查发现，磷酸酶2B型（PPAP 2B，也称为LPP 3或PLPP 3）作为chr 1p32.2的基因，影响冠状动脉疾病（CAD）的风险。此外，内皮PPAP 2B减少与增加CAD易感性。我们最近发现了一种新的机制，将扰动流与还原联系起来通过microRNA介导的机械转导途径在内皮PPAP 2B中：扰动流动激活内皮细胞miR-92 a，其反过来直接抑制PPAP 2B，也通过抑制内皮细胞miR-92 a间接抑制PPAP 2B。激活PPAP 2B的转录因子KLF 2;减少内皮PPAP 2B然后导致增加内皮炎症和受损的单层完整性。此外，先前的研究表明， miR-92 a抑制剂的全身递送在广泛的组织中抑制miR-92 a，并且减少了miR-92 a抑制剂的全身递送。小鼠动脉粥样硬化。尽管这些结果表明，流动敏感的miR 92 a-PPAP 2B途径导致动脉粥样硬化易感的内皮细胞表型，内皮miR 92 a-PPAP 2B途径和动脉粥样硬化形成的体内研究仍不确定。此外，该机制 PPAP 2B中CAD相关的因果变异体通过其发挥作用及其在内皮细胞中的潜在作用。机械转导仍然未被探索。我们已经收集了非常强有力的证据，PPAP 2B基因变异与单向流动一致地促进内皮PPAP 2B。总的目标是阐明的分子收敛内皮miR 92 a-PPAP 2B通路中的CAD遗传易感性和机械转导机制- 的方式，其失调被假设为促进动脉粥样硬化的原因。我们建议的研究- 阐述了三个基本重要的问题：1）内皮miR 92 a-PPAP 2B途径是否与内皮细胞的增殖有关？调节体内动脉粥样硬化？我们在Aim 1中使用新的小鼠模型和创新的纳米颗粒来测试这一点，选择性地调节内皮miR 92 a-PPAP 2B信号传导。2)CAD保护性等位基因在 rs 17114036影响PPAP 2B表达？在目标2中，我们功能性地描述了rs 17114036依赖的在PPAP 2B增强子中使用互补的体内和体外遗传方法。3)什么是附加- KLF 2在调节等位基因特异性PPAP 2B表达中的作用？我们解决这个动态调节目的3中通过KLF 2的机械和药理学刺激来增强含有rs 17114036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

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