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

摘要 左心发育不良综合征是一种死亡率很高的先天性心脏病。婴幼儿 这种综合征是由于左心室发育不全引起的先天性循环问题， 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的开胸手术 恢复体循环即使在手术后，这些患者也会出现心力衰竭和其他疾病。 作为单心室的右心室负荷过重导致的并发症。知之甚少 关于HLHS的病因和致病机制。最近的人类遗传学研究发现， 与HLHS表型相关的RNA结合蛋白RBFOX 2的功能缺失突变。是 目前尚不清楚RBFOX 2如何导致HLHS发育缺陷。这主要是因为我们的 缺乏关于RBFOX 2在心血管发育中的作用及其靶RNA的知识， 胚胎心脏使用我们的Rbfox 2条件性敲除小鼠模型，该模型概括了几种表型， HLHS的细胞和分子特征，我们将解决这些紧迫的和临床相关的问题，利用 遗传、分子/细胞和现有技术定制设计的测序和计算方法。 我们的主要目标是确定RBFOX 2调节的RNA网络有助于 心血管发育，并研究其对HLHS的贡献。我们的工作将决定 RBFOX 2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RBFOX 2调节的HLHS治疗策略， 基因表达在HLHS患者使用修饰的反义寡核苷酸在未来。

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.