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A RasGAP-microRNA connection in cardiac hypertrophy

心脏肥大中的 RasGAP-microRNA 连接

基本信息

批准号：
8764813
负责人：
Maha Abdellatif
金额：
$ 5.09万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8764813
关键词：
Address Adenoviruses Age Binding Binding Proteins Cardiac Cardiovascular Diseases Cell Nucleus Cells Complementary DNA Complex Cytoskeleton Cytosol Data Development Down-Regulation Elements Endothelin Event Exhibits FLNC gene Feedback Fibronectins Gene Expression Gene Targeting Genes Growth Growth Factor Health Heart Heart Hypertrophy Hypertrophy Left Malignant Neoplasms Mediating Membrane Messenger RNA MicroRNAs Minor Mus Muscle Cells Nuclear RNA Outcome Pathway interactions Phosphorylation Play Post-Transcriptional Regulation Protein Binding RNA-Binding Proteins Recombinants Recruitment Activity Regulation Regulator Genes Reporting Repression Role Site Somatomedins Stimulus Stretching Thick Transgenes Transgenic Mice Translations Up-Regulation Ventricular Work filamin in vivo integrin-linked kinase mouse model premature pressure promoter ras GTPase-Activating Proteins research study therapeutic target

项目摘要

DESCRIPTION (provided by applicant): In this proposal we will determine the role of Ras GTPase-activating protein (RasGAP) in regulating microRNA-1 (miR-1) during cardiac hypertrophy. MiR-1 is a post- transcriptional regulator of gene expression that is acutely down-regulated upon induction of hypertrophy by work overload, growth factors, or RasGAP, an outcome that is necessary for myocyte growth. Our preliminary data show that RasGAP SH3-binding protein (G3BP) binds miR-1 in a RasGAP- and Akt-dependent manner. We hypothesize that hypertrophic stimuli induce Akt-mediated G3BP phosphorylation and its subsequent recruitment by RasGAP-filamin complex. This brings it into close proximity to miR-1, where it binds and hydrolyzes premature miR-1. Subsequently, down-regulation of miR- 1 results in upregulation of its targets that include: RasGAP, Cdk9, fibronectin, endothelin, and insulin-like growth factor, among others. These genes play a critical role in the development of cardiac hypertrophy. Thus, our Aims are: 1) to study the mechanism of RasGAP-mediated down-regulation of miR-1 during myocyte hypertrophy. For this aim we will utilize cultured myocytes in conjunction with recombinant cDNA, adenoviruses, and promoter constructs, using stretch as a hypertrophic stimulus to: a. examine the role of G3BP in post-transcriptional regulation of miR-1, b. examine the role of Akt in RasGAP-G3BP-regulated miR-1 stability, c. examine the role of filamin-C in recruitment of RasGAP-G3BP, d. examine the effect of hypertrophy and the RasGAP- activated pathway on transcriptional vs. post-transcriptional regulation of miR-1. Aim 2) to study the role of RasGAP and miR-1 during cardiac hypertrophy in a mouse model.

描述（由申请人提供）：在本提案中，我们将确定Ras gtpase激活蛋白（RasGAP）在心脏肥厚期间调节microRNA-1 （miR-1）中的作用。MiR-1是一种基因表达的转录后调节因子，在超负荷工作、生长因子或RasGAP诱导肥大时，MiR-1会急剧下调，这是肌细胞生长所必需的结果。我们的初步数据显示，RasGAP sh3结合蛋白（G3BP）以RasGAP和akt依赖的方式结合miR-1。我们假设肥厚性刺激诱导akt介导的G3BP磷酸化及其随后被rasgap -丝蛋白复合物募集。这使得它接近miR-1，在那里它结合并水解过早的miR-1。随后，miR- 1的下调导致其靶标上调，包括：RasGAP、Cdk9、纤维连接蛋白、内皮素和胰岛素样生长因子等。这些基因在心肌肥厚的发展中起着关键作用。因此，我们的目的是：1)研究rasgap介导的心肌细胞肥大过程中miR-1的下调机制。为此，我们将利用培养的肌细胞与重组cDNA、腺病毒和启动子结构结合，使用拉伸作为增生性刺激：a.研究G3BP在miR-1转录后调控中的作用，b.研究Akt在RasGAP-G3BP调控的miR-1稳定性中的作用，c.研究丝蛋白c在RasGAP-G3BP募集中的作用，d.研究肥大和RasGAP激活途径对miR-1转录和转录后调控的影响。目的2)研究RasGAP和miR-1在小鼠心肌肥厚模型中的作用。