Role of small RNAs in ischemic tissue repair

小RNA在缺血组织修复中的作用

基本信息

  • 批准号:
    10736743
  • 负责人:
  • 金额:
    $ 58.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-01 至 2028-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Cardiovascular disease (CVD) remains the leading cause of death, and there is a critical need to determine underlying mechanisms and develop novel therapies for treatment. Small Cajal body-specific RNAs (scaRNAs) are evolutionarily conserved non-coding RNAs that guide biochemical modification on specific nucleotides such as pseudouridylation (Ψ) and 2′-O-ribose methylation (2′-OMe). These modifications are essential in the post- transcriptional changes and functions of spliceosomal small nuclear RNAs (snRNA). Recent studies highlight a crucial role of scaRNA in preserving spliceosome fidelity and cardiac development; however, the role of scaRNAs in acute cardiac injury and its repair has not been established. This proposal aims to determine scaRNA’s role in cardiovascular processes in a mouse myocardial infarction (MI) model that could develop new tools for treating MI. Our central hypothesis is that overexpression of scaRNA18 in the post-MI heart promotes positive cardiac remodeling by inducing therapeutic angiogenesis via 2′-OMe of U4 snRNA and regulating Wilms tumor1 (WT1) expression, thereby conferring cardioprotection and improving cardiac function. Our preliminary data demonstrates 1) decreased scaRNA18 expression in post-MI mouse hearts using unbiased small RNA sequencing, 2) scaRNA18 expression exclusively downregulated in isolated cardiac endothelial cells (EC) in post-MI mouse hearts, 3) scaRNA18 knockdown (KD) impairs tube formation and induces apoptosis in mouse cardiac ECs without induced stress, 4) scaRNA18 overexpression enhances EC angiogenesis and inhibits stress-induced EC apoptosis in vitro, 5) scaRNA18-overexpressing cardiac EC extracellular vesicles protect iPSC-cardiomyocyte cell death via angiogenic proteins, 6) 2’-O-methylation levels were reduced in MI hearts and in cardiac ECs from scaRNA18 KD mice, 7) mutant scaRNA18 lacking binding sites to guide 2′-OMe on U4 snRNA induces EC cell apoptosis without induced stress, 8) unbiased mass spectrometry results revealed that scaRNA18 reduces WT1 expression levels in scaRNA18 KD cardiac ECs, 9) WT-1 KD in the presence of scaRNA18 overexpression nullified scaRNA18 mediated EC survival effects, and 10) overexpression of scaRNA18 by VE-cadherin-driven AAV9 reduces infarct size after ex vivo cardiac ischemia/reperfusion injury and improves cardiac function post-MI mice (in vivo). The hypothesis that scaRNA18 is a critical component in cardiac function and repair will be tested in the following three specific aims: in Aim 1, we will define the role of scaRNA18 in cardiac EC function and cardiomyocyte survival; in Aim 2, we will determine the molecular mechanisms by which scaRNA18 regulates cardiac EC function and cardiomyocyte survival, and in Aim 3 we will use post-MI mice to demonstrate the critical role of scaRNA18 in myocardial injury repair. The proposed studies could establish scaRNAs as novel therapeutic targets for MI.
项目摘要 心血管疾病(CVD)仍然是死亡的主要原因,迫切需要确定 潜在的机制,并开发新的治疗方法。小卡哈尔体特异性RNA(scaRNA) 是进化上保守的非编码RNA,可引导特定核苷酸的生化修饰,例如 如假尿苷化(pseudouridylation,PGD)和2′-O-核糖甲基化(2′-OMe)。这些修改在后... 剪接体小核RNA(snRNA)的转录变化和功能。最近的研究强调, scaRNA在保持剪接体保真度和心脏发育中的关键作用;然而,scaRNA的作用 急性心脏损伤及其修复尚未建立。 这 该提案旨在确定scaRNA的作用 在小鼠心肌梗死(MI)模型的心血管过程中, MI.我们的中心假设是心肌梗死后心脏中scaRNA 18的过度表达促进了心肌梗死后心肌细胞的阳性表达。 通过U4 snRNA的2′-OMe诱导治疗性血管生成并调节Wilms tumor 1(WT 1)进行重塑 表达,从而赋予心脏保护和改善心脏功能。我们的初步数据 证明1)使用无偏小RNA在MI后小鼠心脏中降低scaRNA 18表达 测序,2)scaRNA 18表达在分离的心脏内皮细胞(EC)中特异性下调, 3)scaRNA 18敲低(KD)损害小鼠中的管形成并诱导细胞凋亡 4)scaRNA 18过表达增强EC血管生成并抑制 体外应激诱导EC凋亡,5)scaRNA 18过表达的心脏EC细胞外囊泡保护 通过血管生成蛋白导致iPSC-心肌细胞死亡,6)MI心脏中2 '-O-甲基化水平降低 在scaRNA 18 KD小鼠的心脏EC中,7)突变体scaRNA 18缺乏引导U4上2′-OMe的结合位点 snRNA诱导EC细胞凋亡而不诱导应激,8)无偏质谱结果显示, scaRNA 18降低了scaRNA 18 KD心脏EC中的WT 1表达水平,9)在 scaRNA 18过表达使scaRNA 18介导的EC存活效应无效,和10) 通过VE-钙粘蛋白驱动的AAV 9的scaRNA 18减少离体心脏缺血/再灌注损伤后的梗死面积 并改善MI后小鼠的心脏功能(体内)。scaRNA 18是一个关键成分的假设, 心脏功能和修复将在以下三个具体目标中进行测试:在目标1中,我们将定义 scaRNA 18在心脏EC功能和心肌细胞存活中的作用;在目标2中,我们将确定scaRNA 18在心脏EC功能和心肌细胞存活中的分子作用。 scaRNA 18调节心脏EC功能和心肌细胞存活的机制,在Aim 3中, 将使用MI后小鼠来证明scaRNA 18在心肌损伤修复中的关键作用。拟议 研究可以建立scaRNA作为MI的新治疗靶点。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A contemporary review of snoRNAs in cardiovascular health: RNA modification and beyond.
  • DOI:
    10.1016/j.omtn.2023.102087
  • 发表时间:
    2024-03-12
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Jagielski, Noah Peter;Rai, Amit Kumar;Rajan, K. Shanmugha;Mangal, Vatsal;Garikipati, Venkata Naga Srikanth
  • 通讯作者:
    Garikipati, Venkata Naga Srikanth
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Venkata Naga Srikanth Garikipati其他文献

Long-lasting sex-specific alteration in left ventricular cardiac transcriptome following gamma and simGCRsim radiation
  • DOI:
    10.1038/s41598-025-89815-2
  • 发表时间:
    2025-02-18
  • 期刊:
  • 影响因子:
    3.900
  • 作者:
    Roksana Zakharyan;Siras Hakobyan;Agnieszka Brojakowska;Suren Davitavyan;Ani Stepanyan;Tamara Sirunyan;Gisane Khachatryan;Mary K. Khlgatian;Malik Bisserier;Shihong Zhang;Susmita Sahoo;Lahouaria Hadri;Venkata Naga Srikanth Garikipati;Arsen Arakelyan;David A. Goukassian
  • 通讯作者:
    David A. Goukassian
Muscle-specific miR-499-5p delivered by small extracellular vesicles impairs endothelial function and ischemic hindlimb recovery in diabetic mice
  • DOI:
    10.1186/s12933-025-02825-2
  • 发表时间:
    2025-07-10
  • 期刊:
  • 影响因子:
    10.600
  • 作者:
    Zhongjian Cheng;May M. Truongcao;Vandana Mallaredy;Maria Cimini;Charan Thej;Darukeshwara Joladarashi;Carolina Gonzalez;Cindy Benedict;Suresh K. Verma;Venkata Naga Srikanth Garikipati;Raj Kishore
  • 通讯作者:
    Raj Kishore
Evaluating sex-specific responses to western diet across the lifespan: impact on cardiac function and transcriptomic signatures in C57BL/6J mice at 530 and 640/750 days of age
  • DOI:
    10.1186/s12933-024-02565-9
  • 发表时间:
    2024-12-28
  • 期刊:
  • 影响因子:
    10.600
  • 作者:
    Ani Stepanyan;Agnieszka Brojakowska;Roksana Zakharyan;Siras Hakobyan;Suren Davitavyan;Tamara Sirunyan;Gisane Khachatryan;Mary K. Khlgatian;Malik Bisserier;Shihong Zhang;Susmita Sahoo;Lahouaria Hadri;Amit Rai;Venkata Naga Srikanth Garikipati;Arsen Arakelyan;David A. Goukassian
  • 通讯作者:
    David A. Goukassian

Venkata Naga Srikanth Garikipati的其他文献

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