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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(申请人提供)：肺动脉高压(PAH)的特征是肺血管阻力增加，阻碍右室射血，导致右室衰竭。PAH是一种严重的疾病，无法治愈。原发性PAH是一种罕见的进展性疾病，4年内死亡率为30%。骨形态发生蛋白受体II(BMPRII)是转化生长因子2(TGF2)受体家族中的一员，最近在80%以上的家族性PAH患者和30%的散发性PAH患者中发现了BMPRII的种系突变。该应用的长期目标是了解BMPRII突变促进PAH发病的分子机制(S)。这一应用的假设是，BMPR2及其下游信号对于维持正常的肺血管结构和功能是必不可少的。我们以前已经证明，TGF2家族的生长因子，TGF2s和BMPs，通过诱导VSMC特异性基因的表达，促进肺动脉平滑肌细胞(PASMCs)从合成表型向收缩表型的转换。我们最近证实，经TGF2或BMP处理后，PASMCs中microRNA-21(miR-21)的表达迅速被诱导。MIR-21属于一个被称为microRNAs(MiRNAs)的短的、非编码的单链RNAs(SsRNAs)家族，它通过以序列特异性的方式靶向mRNAs来调节基因的表达，导致翻译抑制或mRNA降解。在PASMCs中诱导miR-21导致程序性细胞死亡4(PDCD4)的下调，进而导致VSMC特异性基因表达的上调。有趣的是，我们的数据表明，TGF2和BMP通过促进细胞核中的DROSHA微处理器复合体将miR-21的初级转录产物(pri-miR-21)加工成前体miR-21(前miR-21)，从而在转录后介导miR-21的诱导。本应用的主要目的是研究TGF2和BMP对miR-21生物合成的调控机制，这对于理解TGF2/BMP介导的PAH发病机制的分子机制是至关重要的。为此，SA1将研究Smad与特定的pri-miRNAs的关联机制。SA2将阐明Smad蛋白在TGF2/BMP调控的pri-miR-21加工中的作用。SA3将探索miR-21靶向PDCD4在调节血管平滑肌表型中的作用。这一应用研究了TGF2/BMP-Smad信号通路对基因调控的未知机制，这对于理解PAH的发病机制和开发新的治疗方法是基础的。公共卫生相关性：血管平滑肌细胞(VSMC)的部分特征是它们能够在静止的、分化的“收缩”状态和增殖的、分化较少的“合成”状态之间调节其表型；此外，当血管受损时，VSMC采用合成表型作为正常修复过程的一部分。提示VSMCs的表型改变参与了肺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、淋巴管肌瘤病和肺动脉高压(PAH)。这一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具有重要意义。