Function of miR-451 in angiogenesis, hematopoiesis and cardiogenesis

描述（由申请人提供）：MicroRNAs （miRs）是一种小的非编码rna，在转录后抑制基因表达，并在广泛的生物学过程中发挥重要作用，包括胚胎发育过程中的细胞命运决定和器官发生。一些在心血管发育中起作用的miRs已经被研究，揭示了它们在这一发育过程的微妙调节中的重要性。更多参与这一过程的miRs正在研究中，总体结果将拓宽我们对心血管系统形成的理解，最终有利于人类心血管疾病的诊断、预防和治疗。我们的长期目标是鉴定这些miRs并阐明这些miRs如何调节心血管发展的潜在机制。我们的初步研究表明，miR-451是一种从心源性miR筛选中鉴定出的高度保守的miR，在胚胎发生过程中在内皮细胞和血细胞谱系中广泛表达，在体外胚胎干细胞分化过程中具有不同的功能，促进内皮细胞和血细胞的分化，同时阻断心肌细胞的分化。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在胚胎发生过程中通过调节各自细胞系的规范来参与血管生成、造血和心脏生成。为了验证这一假设，提出了三个具体目标：1。鉴定miR-451敲除小鼠的心血管表型。2. 探讨miR-451在发育过程中内皮细胞、血液细胞和心脏细胞谱系分化中的作用。3. 阐明miR-451在心血管发育中功能的分子机制。拟议的研究不仅可以深入了解miR-451在心血管发育中的功能机制，还可以为mir在早期发育过程中调节的细胞谱系决定提供有价值的信息。

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.