Function of miR-451 in angiogenesis, hematopoiesis and cardiogenesis

描述(申请人提供)：microRNAs(MiRs)是转录后抑制基因表达的非编码小RNA，在广泛的生物学过程中发挥重要作用，包括决定细胞命运和胚胎发育期间的器官发生。已经研究了几个在心血管发育中起作用的MIR，揭示了它们在这一发育过程的微妙调控中的重要性。更多的MIR参与这一过程的研究正在进行中，总体结果将拓宽我们对心血管系统形成的理解，最终有助于人类心血管疾病的诊断、预防和治疗。我们的长期目标是确定这些MIR，并阐明这些MIR如何调节心血管发育的潜在机制。我们的初步研究表明，miR-451是一种高度保守的miR，在胚胎发育过程中广泛表达于血管内皮细胞和血细胞系，在体外胚胎干细胞分化过程中通过促进内皮细胞和血细胞的分化而抑制心肌细胞的分化，具有独特的功能。这一功能至少部分是通过下调靶Acvr2a和上调Wnt信号来实现的。然而，miR-451在心血管发育中的体内功能尚未被研究。因此，本项目的假设是miR-451在胚胎发育过程中通过调节各自细胞系的特性而在血管生成、造血和心脏生成中发挥作用。为了验证这一假说，提出了三个具体目标：1.鉴定miR-451基因敲除小鼠的心血管表型。2.探讨miR-451在发育过程中对内皮细胞、血液细胞和心脏细胞谱系的调控作用。3.阐明miR-451‘S在心血管发育中作用的分子机制。这些研究不仅可以深入了解miR-451在心血管发育中的作用机制，还可以为早期发育过程中miR调控的细胞谱系决定提供有价值的信息。 公共卫生相关性：我们建议进行一项研究，以了解miR-451在胚胎发育过程中的血管生成、造血和心脏生成中的功能。我们的基础研究将有助于了解人类疾病是如何发展以及如何治愈的。

DESCRIPTION (provided by applicant): MicroRNAs (miRs) are small non-coding RNAs that post-transcriptionally repress gene expression and play important roles in a wide range of biological processes, including cell fate determination and organogenesis during embryonic development. Several miRs that function in cardiovascular development have been studied revealing their importance in the delicate regulation of this developmental process. More miRs involved in this process are being studied and the overall results will broaden our understanding of the formation of cardiovascular system and eventually benefit the diagnosis, prevention and therapy of human cardiovascular diseases. Our long-term objective is to identify these miRs and elucidate the underlying mechanism of how these miRs regulate cardiovascular development. Our preliminary studies have demonstrated that miR-451, a highly conserved miR identified from a screen for cardiogenic miRs, is expressed extensively in endothelial and blood cell lineages during embryogenesis and has distinct functions during in vitro embryonic stem cell differentiation by promoting the differentiation of endothelial and blood cells while blocking the differentiation of cardiomyocytes. This function is achieved at least partially through the downregulation of target Acvr2a and upregulation of Wnt signaling. However, the in vivo function of miR-451 in cardiovascular development has not been investigated. Therefore, the hypothesis of this project is that miR-451 functions in angiogenesis, hematopoiesis and cardiogenesis during embryogenesis by regulating the specification of respective cell lineages. To test this hypothesis, three specific aims are proposed: 1. To identify the cardiovascular phenotype of miR-451 knockout mice. 2. To investigate the role of miR-451 in the specification of endothelial, blood and cardiac cell lineages during development. 3. To elucidate molecular mechanism underlying miR-451's function in cardiovascular developmental. The proposed studies should not only gain insights into the mechanisms of miR-451 functions in cardiovascular development, but also provide valuable information on the cell lineage determination regulated by miRs during early development. PUBLIC HEALTH RELEVANCE: We propose a study to understand the function of miR-451 in angiogenesis, hematopoiesis and cardiogenesis during embryogenesis. Our basic research will help to understand how human diseases develop and how they can be cured.