Investigating the Requirement of microRNAs in VEGF Signaling In Vivo.

描述（由申请人提供）：在发育和疾病过程中，特定靶点的调控如何影响单个microRNAs （miRNAs）的功能库是发育生物学的一个核心问题。最近的研究表明，在单个细胞的背景下，mirna促进其靶标的抑制。miR-1/206是一种肌肉特异性miRNA，在斑马鱼肌肉发育过程中负责调控bb0 - 54%的靶mrna。然而，在某些体中miR-1/206功能的丧失也会导致周围节段动脉的生长和增殖增加。这提出了一个有趣的可能性，即mirna可能在调节组织间的串扰中发挥作用。对参与血管生成的肌肉表达基因的序列分析表明，VEGF-A是miR-1/206的潜在靶标，并且这种调控在脊椎动物中是保守的。因此，本项目的目标是通过以下方式了解单个miRNA/靶标相互作用如何调节脊椎动物发育过程中的基因表达：1)建立miR-1/206在体内血管发育中的作用。2)研究miR-1/206对vegfA基因的依赖性调控。3)在血管发育过程中，在miR-1/206和VEGF-A信号传导的背景下，测试个体miRNA/靶标相互作用的生理相关性。为了更好地理解miRNA/靶标相互作用如何调节发育过程中的信号通路，我们将深入了解这些相互作用如何促进正常发育，以及这种相互作用的失调如何导致人类疾病和疾病。

DESCRIPTION (provided by applicant): The problem of how the regulation of specific targets contributes to the functional repertoire of individual microRNAs (miRNAs) during development and disease is a central question in developmental biology. Recent studies have demonstrated that miRNAs promote the repression of their targets in the context of a single cell. miR-1/206 is a muscle-specific miRNA and is responsible for the regulation of >54% target mRNAs during muscle development in zebrafish. However, loss of miR-1/206 function in somites also results in increased growth and proliferation in the surrounding segmental arteries. This presents the intriguing possibility that miRNAs may play a role in modulating cross-talk between tissues. Sequence analysis of muscle-expressed genes involved in angiogenesis revealed that VEGF-A is a potential miR-1/206 target and that this regulation is conserved among vertebrates. The goal of this project is therefore to understand how individual miRNA/target interactions regulate gene expression during vertebrate development by: 1) Establishing the role of miR-1/206 in vascular development in vivo. 2) Studying miR-1/206 dependent regulation of vegfA genes. 3) Testing the physiological relevance of individual miRNA/target interactions in the context of miR-1/206 and VEGF-A signaling during vascular development. In better understanding how miRNA/target interactions regulate signaling pathways during development, we will gain insight how these interactions contribute to normal development as well as how dysregulation of this interaction may contribute to human disorders and diseases. PUBLIC HEALTH RELEVANCE: A pivotal step in tumor progression and metastasis is the invasion or co-option of normal capillaries and their proliferation in tumors. Because the signaling mechanisms are shared between normal development and the pathological state, the study of embryonic blood vessel development is of great relevance. In addition, up-regulation of VEGF in humans leads to age-related macular degeneration and diabetic retinopathy. This study has the potential to provide fundamental insights into the role miRNAs play in human diseases, tumor angiogenesis and cancer metastasis.