Role of miRNAs in Vascular Physiology

miRNA 在血管生理学中的作用

基本信息

批准号：
8266380
负责人：
Akiko Hata
金额：
$ 38.24万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8266380
关键词：
Adopted Aftercare Anabolism Angioplasty Apoptosis Arteries Atherosclerosis BMPR2 gene Biogenesis Blood Blood Vessels Bone Morphogenetic Proteins Cardiovascular Diseases Cell Nucleus Complex Consensus Data Development Disease Down-Regulation Etiology Exercise Exhibits Failure Family Gene Expression Gene Expression Regulation Gene Targeting Genes Germ-Line Mutation Goals Growth Factor Hypoxia Inherited Lung Lymphangioleiomyomatosis Maintenance Maps Mediating Messenger RNA MicroRNAs Microprocessor Molecular Mutation Pathogenesis Pathway interactions Patients Penetrance Phenotype Physiology Process Progressive Disease Proteins Pulmonary Vascular Resistance Pulmonary artery structure RNA Binding Regulation Right ventricular structure Role Signal Pathway Signal Transduction Smad Proteins Smad protein Smooth Muscle Myocytes Stenosis Structure Subgroup Transcript Transforming Growth Factors Translational Repression Transplantation Vascular Diseases Vascular Smooth Muscle Vascular remodeling Ventricular autosomal dominant trait bone morphogenetic protein 2 bone morphogenetic protein receptor type II mRNA Transcript Degradation member migration mortality novel pressure public health relevance pulmonary arterial hypertension receptor repaired response restenosis

项目摘要

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is characterized by an increase in pulmonary vascular resistance that impedes ejection of blood by the right ventricle, leading to right ventricular failure. PAH is a serious condition for which there is no cure. Primary PAH is a rare but progressive disease with a mortality of 30 percent over 4 years. Recently germline mutations in bone morphogenetic protein receptor type II (BMPRII), a member of the transforming growth factor 2 (TGF2) receptor family, have been found in over 80 percent of familial PAH patients and in 30 percent of sporadic cases of PAH. The long-term objective of this application is to understand the molecular mechanism(s) by which BMPRII mutations contribute to the pathogenesis of PAH. The hypothesis of this application is that BMPR2 and its downstream signal are essential for maintenance of a normal pulmonary vascular structure and function. We have shown previously that the TGF2 family of growth factors, TGF2s and BMPs, promote a switch from a "synthetic" to "contractile" phenotype of pulmonary artery smooth muscle cells (PASMCs) by inducing the expression of VSMC-specific genes. We recently demonstrated that the expression of microRNA-21 (miR-21) is rapidly induced after a treatment with TGF2 or BMP in PASMCs. MiR-21 belongs to a family of short, noncoding, single-stranded RNAs (ssRNAs) called microRNAs (miRNAs) that regulate gene expression by targeting mRNAs in a sequence-specific manner, causing translational repression or mRNA degradation. Induction of miR-21 in PASMCs leads to downregulation of Programmed Cell Death 4 (PDCD4) which in turn leads to the elevation of VSMC-specific gene expression. Interestingly, our data indicate that TGF2 and BMP mediate miR-21 induction post- transcriptionally by promoting the processing of primary transcripts of miR-21 (pri-miR-21) into precursor miR- 21 (pre-miR-21) by the Drosha microprocessor complex in the nucleus. The main goal of this application is to investigate a mechanism of regulation of miR-21 biosynthesis by TGF2 and BMP, which is crucial for understanding a molecular mechanism of TGF2/BMP-mediated phenotype switch underlying the pathogenesis of PAH. To this end, SA1 will examine a mechanism of association of Smads with specific pri-miRNAs. SA2 will elucidate a role of Smad proteins in the TGF2/BMP-regulated pri-miR-21 processing. SA3 will explore a role of miR-21 target PDCD4 in the regulation of vascular smooth muscle phenotype. This application investigates the previously unexplored mechanism of gene regulation by the TGF2/BMP-Smad signaling pathway which is fundamental for understanding the pathogenesis and development of novel therapies for PAH. PUBLIC HEALTH RELEVANCE: Vascular smooth muscle cells (VSMC) are characterized in part by their ability to modulate their phenotype between a quiescent, differentiated "contractile" state and a proliferative, less differentiated, "synthetic" state; further, upon vascular damage, VSMCs adopt the synthetic phenotype as part of a normal repair process. It is suggested that the phenotypic modulation of VSMCs contributes to various disorders in the pulmonary and systemic arteries, including post-angioplasty re-stenosis, transplant vasculopathy, atherosclerosis, lymphangioleiomyomatosis, and pulmonary arterial hypertension (PAH). This application will elucidate a novel mechanism of regulation of VSMC phenotype in normal physiology, which is of fundamental importance in understanding the etiology of cardiovascular disorders.

描述（由申请人提供）：肺动脉高压（PAH）的特征是肺血管阻力增加，阻碍右心室射血，导致右心室衰竭。 PAH 是一种无法治愈的严重疾病。原发性 PAH 是一种罕见但进行性疾病，4 年内死亡率为 30%。最近，在超过 80% 的家族性 PAH 患者和 30% 的散发性 PAH 病例中发现了 II 型骨形态发生蛋白受体 (BMPRII) 的种系突变，该受体是转化生长因子 2 (TGF2) 受体家族的成员。本申请的长期目标是了解 BMPRII 突变导致 PAH 发病机制的分子机制。本申请的假设是 BMPR2 及其下游信号对于维持正常的肺血管结构和功能至关重要。我们之前已经证明，TGF2 生长因子家族、TGF2 和 BMP 通过诱导 VSMC 特异性基因的表达，促进肺动脉平滑肌细胞 (PASMC) 从“合成”表型向“收缩”表型的转变。我们最近证明，在 PASMC 中用 TGF2 或 BMP 处理后，microRNA-21 (miR-21) 的表达迅速被诱导。 MiR-21 属于称为 microRNA (miRNA) 的短非编码单链 RNA (ssRNA) 家族，它通过以序列特异性方式靶向 mRNA 来调节基因表达，导致翻译抑制或 mRNA 降解。 PASMC 中 miR-21 的诱导导致程序性细胞死亡 4 (PDCD4) 下调，进而导致 VSMC 特异性基因表达升高。有趣的是，我们的数据表明，TGF2 和 BMP 通过促进 Drosha 将 miR-21 (pri-miR-21) 的初级转录物加工成前体 miR-21 (pre-miR-21) 来介导转录后 miR-21 诱导。原子核中的微处理器复合体。本申请的主要目标是研究TGF2和BMP调节miR-21生物合成的机制，这对于理解PAH发病机制中TGF2/BMP介导的表型转换的分子机制至关重要。为此，SA1 将研究 Smad 与特定 pri-miRNA 的关联机制。 SA2 将阐明 Smad 蛋白在 TGF2/BMP 调节的 pri-miR-21 加工中的作用。 SA3将探索miR-21靶标PDCD4在血管平滑肌表型调节中的作用。该应用研究了先前未探索的 TGF2/BMP-Smad 信号通路的基因调控机制，这对于了解 PAH 的发病机制和新疗法的开发至关重要。公共健康相关性：血管平滑肌细胞 (VSMC) 的部分特征在于其能够在静止、分化的“收缩”状态和增殖、分化程度较低的“合成”状态之间调节其表型；此外，血管损伤后，VSMC 会采用合成表型作为正常修复过程的一部分。有人认为，VSMC 的表型调节会导致肺动脉和全身动脉的各种疾病，包括血管成形术后再狭窄、移植血管病变、动脉粥样硬化、淋巴管平滑肌瘤病和肺动脉高压 (PAH)。该应用将阐明正常生理学中 VSMC 表型调节的新机制，这对于理解心血管疾病的病因学具有根本重要意义。