Role of small RNAs in ischemic tissue repair

小RNA在缺血组织修复中的作用

• 批准号: 10736743
• 负责人: Venkata Naga Srikanth Garikipati
• 金额: $ 58.25万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10736743
• 关键词: Accounting; Acute; Alternative Splicing; Angiogenic Proteins; Apoptosis; Attenuated; Binding Sites; Biochemical; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Death; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cessation of life; Data; Development; Diagnosis; Endothelial Cells; Guide RNA; Heart; Heart Injuries; Heart failure; Hypoxia; Impairment; In Vitro; Induction of Apoptosis; Infarction; Innovative Therapy; Ischemia; Knowledge; Left Ventricular Function; Length; Mass Spectrum Analysis; Mediating; Messenger RNA; Methylation; Modeling; Modification; Molecular; Mus; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Nephroblastoma; Nucleotides; Outcome; Patients; Pattern; Play; Post-Transcriptional Regulation; Process; Prognosis; Public Health; Quality of life; RNA; Regimen; Reperfusion Injury; Ribose; Role; Small Nuclear RNA; Small Nucleolar RNA; Small RNA; Spliceosomes; Stress; Testing; Therapeutic; Tube; U4 Small Nuclear Ribonucleoproteins; U4 small nuclear RNA; United States; Untranslated RNA; WT1 gene; angiogenesis; cadherin 5; cardiac repair; cardiogenesis; cardioprotection; cardiovascular disorder therapy; effective therapy; extracellular vesicles; gain of function; heart function; improved; in vivo; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; injury and repair; innovation; insight; knock-down; migration; mutant; myocardial injury; neovascularization; new therapeutic target; novel; novel diagnostics; novel therapeutics; overexpression; paracrine; posttranscriptional; preservation; promoter; repaired; reparative capacity; therapeutic RNA; therapeutic angiogenesis; tissue repair; tool; transcriptome sequencing; treatment strategy

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.

项目总结

项目成果

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: MOLECULAR THERAPY NUCLEIC ACIDS
• 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