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Role of snoRNAs in regulation of cardiac hypertrophy

snoRNA 在调节心脏肥大中的作用

基本信息

批准号：
9351563
负责人：
Christopher Lee Holley
金额：
$ 7.95万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9351563
关键词：
Address Animal Model Antioxidants Antisense Oligonucleotides Aortic Valve Stenosis Biological Models Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cause of Death Cell Size Cellular Stress Clinical Clinical Treatment Code Data Development Disease model Drug Targeting Enzymes Foundations Generations Genetic Genetic Transcription Genetically Engineered Mouse Goals Heart Heart Diseases Heart Hypertrophy Heart failure Hypertension Hypertrophy In Vitro Investigation Knock-out Knockout Mice Link Lipids Mediating Mediator of activation protein Messenger RNA Modeling Modification Mus Myocardial Ischemia NADPH Oxidase Neonatal Normal Cell Nuclear Nucleotides Oxidative Stress Pathologic Pathway interactions Phenotype Phenylephrine Physiological Play Process Protein Isoforms Rattus Reactive Oxygen Species Regulation Research Resistance Rest Role Small Nucleolar RNA Stimulus Testing Tissues Toxic effect United States Untranslated RNA Work cell determination cell type constriction disability in vitro Model in vivo in vivo Model knock-down knockout animal loss of function new therapeutic target novel pressure response targeted treatment transcriptome sequencing

项目摘要

ABSTRACT Pathologic cardiac hypertrophy is a common feature in many cardiovascular diseases, such as hypertension, aortic stenosis, ischemic heart disease, and heart failure. As such, the regulation of cardiomyocyte hypertrophy has been extensively studied, and it is regulated, in part, by reactive oxygen species (ROS). Despite this, there have been no successful clinical treatments that specifically target ROS or cardiovascular oxidative stress as a pathologic mechanism. The aim of this proposal is to investigate a novel and drug-targetable pathway that regulates ROS and oxidative stress via non-coding RNAs (ncRNA) known as snoRNA (small nucleolar RNA). These short ncRNA canonically act as “guides” for enzymes that catalyze nucleotide modifications on target RNAs. Recently, four snoRNAs from the Rpl13a locus have been identified as unexpected regulators of ROS and oxidative stress, both in vitro and in vivo. Since cardiac hypertrophy is regulated by ROS, we hypothesized that the Rpl13a snoRNAs would be important for this process. Preliminary data now shows that mice lacking the Rpl13a snoRNAs are, in fact, resistant to hypertrophy and pathologic cardiac remodeling in the setting of pressure overload from transverse aortic constriction. Moreover, the loss of these snoRNAs also results in unusually small hearts in young mice, suggesting that the Rpl13a snoRNAs may be general regulators of cardiomyocte size. The research proposed in this application will build on these important physiologic findings in order to understand the mechanisms by which the Rpl13a snoRNAs influence ROS, oxidative stress, and cardiac cell size. Specifically, Aim 1 will identify and validate transcriptional networks that are regulated by the Rpl13a snoRNAs, using in vitro and in vivo models of cardiomyocyte hypertrophy combined with RNA-seq to quantitatively assess both coding and non-coding RNAs. Aim 2 will specifically examine the relationship between Nox4 and the Rpl13a snoRNAs in the ROS-mediated regulation of cardiomyocyte size, both for the determination of normal cell size and hypertrophy. The preliminary data generated here will be used to support a larger R01 application to directly address the mechanisms by which snoRNAs regulate ROS and oxidative stress in relation to cardiac cell size and hypertrophy.

摘要