The role of RNA binding proteins in heart development and congenital heart defects

RNA结合蛋白在心脏发育和先天性心脏缺陷中的作用

基本信息

批准号：
10827567
负责人：
MUGE NESLIHAN KUYUMCU-MARTINEZ
金额：
$ 73.38万
依托单位：
UNIVERSITY OF VIRGINIA
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：
2023-04-12 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10827567
关键词：
3&apos Untranslated Regions Ablation Address Adhesions Advanced Development Affect Alternative Splicing Antisense Oligonucleotides Aorta Binding Cardiac Cardiac Myocytes Cardiac Surgery procedures Cardiovascular system Cell Adhesion Cell Proliferation Cell physiology Cells Circulation Common Ventricle Complementary DNA Congenital Heart Defects Custom Defect Development Developmental Process Disease Embryonic Heart Endothelial Cells Etiology Exhibits Extracellular Matrix Focal Adhesions Future Gene Expression Generations Genes Genetic Genetic study Goals Health Heart Heart Transplantation Heart failure Human Genetics Hypoplastic Left Heart Syndrome Impairment Infant Introns Knock-in Knockout Mice Knowledge Left Left ventricular structure Length Link Mediating Mesenchymal Mitochondria Mitral Valve Molecular Mus Myoblasts Myocardial Neurofibromin 2 Operative Surgical Procedures Pathogenicity Pathology Patients Phenotype Poly A Polyadenylation Proliferating Property Protein Isoforms RNA RNA-Binding Proteins Regulation Reporting Right ventricular structure Role Series Side Signal Pathway Signal Transduction Site Syndrome Techniques Testing Therapeutic Tissues Transcript Work aortic valve cardiogenesis cell motility clinically relevant conditional knockout congenital heart disorder design gene correction gene function innovation insight loss of function loss of function mutation mRNA Precursor migration mortality mouse model mutant nanopore novel novel therapeutics prevent

项目摘要

ABSTRACT Hypoplastic left heart syndrome (HLHS) is a congenital heart disease with a high mortality rate. Infants with this syndrome are born with circulation problems due to hypoplasia of the left part of the heart that includes aorta, left ventricle, mitral valve and aortic valve. Infants may need to undergo a series of open-heart surgeries to restore systemic circulation. Even after the surgeries, these patients can develop heart failure and other complications due to the overload on the right ventricle that serves as the single ventricle. Very little is known about the etiology and pathogenic mechanisms of HLHS. Recent human genetic studies identified de novo loss of function mutations in the RNA binding protein RBFOX2 that are linked to the HLHS phenotype. It is currently unknown how RBFOX2 contributes to HLHS developmental defects. This is mainly because of our lack of knowledge regarding the role of RBFOX2 in cardiovascular development and its target RNAs in the embryonic heart. Using our Rbfox2 conditional knockout mouse model, which recapitulates several phenotypic, cellular, and molecular features of HLHS, we will address these urgent and clinically relevant questions utilizing genetic, molecular/cellular and state-of-the art custom designed sequencing and computational approaches. Our main goal is to determine the mechanisms by which RBFOX2-regulated RNA networks contribute to cardiovascular development and investigate their contributions to HLHS. Our work will determine the underlying mechanisms of HLHS developmental defects caused by loss of RBFOX2. Ultimately, our findings will advance development of innovative HLHS therapeutic strategies by restoring aberrant RBFOX2-regulated gene expression in HLHS patients using modified antisense oligonucleotides in the future.

抽象的左心发育不良综合征（HLHS）是一种死亡率很高的先天性心脏病。婴儿患有这种综合征由于左心发育不全而先天性出现循环问题，其中包括主动脉、左心室、二尖瓣和主动脉瓣。婴儿可能需要接受一系列心脏直视手术以恢复全身循环。即使在手术后，这些患者也可能出现心力衰竭和其他症状由于作为单心室的右心室超负荷而引起的并发症。知之甚少关于HLHS的病因和发病机制。最近的人类遗传学研究从头发现与 HLHS 表型相关的 RNA 结合蛋白 RBFOX2 的功能缺失突变。这是目前尚不清楚 RBFOX2 如何导致 HLHS 发育缺陷。这主要是因为我们缺乏关于RBFOX2在心血管发育中的作用及其靶RNA的了解胚胎心脏。使用我们的 Rbfox2 条件敲除小鼠模型，该模型概括了几种表型， HLHS 的细胞和分子特征，我们将利用这些紧迫的和临床相关的问题遗传、分子/细胞和最先进的定制设计测序和计算方法。我们的主要目标是确定 RBFOX2 调节的 RNA 网络促进的机制心血管发育并研究它们对 HLHS 的贡献。我们的工作将决定 RBFOX2 缺失导致 HLHS 发育缺陷的潜在机制。最终，我们的发现将通过恢复异常的 RBFOX2 调节来促进创新 HLHS 治疗策略的开发未来使用修饰的反义寡核苷酸在 HLHS 患者中进行基因表达。