Investigating the Requirement of microRNAs in VEGF Signaling In Vivo.

描述（由申请人提供）：在发育和疾病期间，特定靶标的调节如何有助于个体microRNA（miRNAs）的功能库的问题是发育生物学中的中心问题。最近的研究表明，在单个细胞的情况下，miRNA促进其靶点的抑制。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节>54%的靶mRNA。然而，体节中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。这提出了一种有趣的可能性，即miRNA可能在调节组织之间的串扰中发挥作用。参与血管生成的肌肉表达基因的序列分析显示，VEGF-A是一个潜在的miR-1/206靶点，并且这种调控在脊椎动物中是保守的。因此，本项目的目标是了解个体miRNA/靶标相互作用如何在脊椎动物发育过程中调节基因表达：1）确定miR-1/206在体内血管发育中的作用。2)研究vegfA基因的miR-1/206依赖性调控。3)在血管发育期间miR-1/206和VEGF-A信号传导的背景下测试单个miRNA/靶标相互作用的生理相关性。在更好地了解miRNA/靶相互作用如何在发育过程中调节信号通路，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。 公共卫生相关性：肿瘤进展和转移的关键步骤是肿瘤中正常毛细血管的侵入或共选择及其增殖。由于正常发育和病理状态之间的信号传导机制是共享的，因此胚胎血管发育的研究具有重要意义。此外，VEGF在人类中的上调导致年龄相关性黄斑变性和糖尿病视网膜病变。这项研究有可能为miRNAs在人类疾病、肿瘤血管生成和癌症转移中的作用提供基本的见解。

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.