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Role of snoRNAs in regulation of cardiac hypertrophy

Role of snoRNAs in regulation of cardiac hypertrophy
snoRNA 在调节心脏肥大中的作用
批准号:
9351563
负责人:
Christopher Lee Holley
金额:
$7.95万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-15 至 2018-08-31

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中文摘要
翻译
摘要 病理性心肌肥大是许多心血管疾病的共同特征,如高血压, 主动脉瓣狭窄、缺血性心脏病和心力衰竭。因此,心肌细胞肥大的调节 已经被广泛研究,并且它部分地由活性氧(ROS)调节。尽管如此,在 目前还没有成功的临床治疗方法,专门针对ROS或心血管氧化应激, 病理机制 该提案的目的是研究一种新的和药物靶向的途径,调节ROS, 氧化应激通过非编码RNA(ncRNA),称为snoRNA(小核仁RNA)。这些短的ncRNA 作为催化靶RNA上核苷酸修饰的酶的“向导”。近日,四 来自Rp 113 a基因座的snoRNA已被鉴定为ROS和氧化应激的意想不到的调节剂, 无论是在体外还是在体内。 由于心肌肥大受ROS调节,我们假设Rpl 13 a snoRNA可能是重要的 for this process过程.初步的数据显示,缺乏Rpl 13 a snoRNA的小鼠实际上是对 横主动脉压力超负荷时心肌肥厚和病理性心脏重构 收缩。此外,这些snoRNA的丢失也会导致年轻小鼠的心脏异常小, 提示Rp 113 a snoRNA可能是心肌细胞大小的一般调节因子。研究提出 在本申请中,将建立在这些重要的生理学发现的基础上, 其中Rp 113 a snoRNA影响ROS、氧化应激和心脏细胞大小。具体而言,目标1将 鉴定和验证由Rp 113 a snoRNA调控的转录网络,使用体外和体内 心肌细胞肥大的体内模型与RNA-seq相结合,以定量评估编码和 非编码RNA。目的2将具体地检查Nox 4和Rpl 13 a snoRNA之间的关系, ROS介导的心肌细胞大小调节,用于测定正常细胞大小, 肥厚此处生成的初步数据将用于支持更大的R 01应用程序, 阐明snoRNA调节ROS和氧化应激与心肌细胞大小的关系的机制 和肥大。
英文摘要
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.
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The Role of RNA Modifications in Heart Failure
  • 批准号:
    9918955
  • 项目类别:
  • 资助金额:
    $36.23万
  • 财政年份:
    2019
  • 负责人:
    Christopher Lee Holley
  • 依托单位:
SnoRNA-guided modifications of mRNA
  • 批准号:
    10307575
  • 项目类别:
  • 资助金额:
    $32.2万
  • 财政年份:
    2019
  • 负责人:
    Christopher Lee Holley
  • 依托单位:
The Role of RNA Modifications in Heart Failure
  • 批准号:
    10375404
  • 项目类别:
  • 资助金额:
    $36.23万
  • 财政年份:
    2019
  • 负责人:
    Christopher Lee Holley
  • 依托单位:
SnoRNA-guided modifications of mRNA
  • 批准号:
    10063945
  • 项目类别:
  • 资助金额:
    $32.2万
  • 财政年份:
    2019
  • 负责人:
    Christopher Lee Holley
  • 依托单位:
海外基金