MicroRNAs in Endothelial Cell Activation.

描述（由申请人提供）：微小RNA（miRNA）是短的非编码RNA，其主要通过转录后抑制来控制基因表达，涉及多种生理和病理过程的控制。最近，我们描述了内皮miRNAs在血管生物学的中心方面的作用，如血管生成和炎症，这些过程需要协调众多复杂的信号通路，其中内皮细胞（EC）既是积极的参与者，又是调节者。内皮细胞活化对于导致炎症、血管重塑和血管生长的许多血管过程是必不可少的。细胞因子，如血管内皮生长因子（VEGF）和肿瘤坏死因子（TNF）介导这种激活，并分别在控制血管生成和炎症反应中发挥重要作用。miRNA的功能受影响其生物发生或活性的细胞外因子调节，从而微调生物反应的调节。然而，我们对EC中microRNA调控机制的理解是有限的。我们假设，生理水平的miRNA的调节条件下，如炎症或血管生成激活，以协调特定的基因表达程序在EC。我们提出了三个目标：目标1：确定VEGF和TNF调节内皮细胞中miRNA水平的分子机制。目的2：探讨VEGF和TNF调控的miRNA对EC靶点和功能的调控作用。目的3：明确VEGF和TNF调控的miRNAs在体内的作用.总之，这些目标的完成将提供关键的洞察控制内皮细胞miRNA的生物合成和活性的基本调控机制，以及它们对EC生物学的影响。了解涉及EC miRNA及其靶点的复杂网络，导致基因表达的协调模式，无疑将有助于更好地理解控制EC激活的细胞和分子机制，并可能通过调节miRNA活性来确定调节内皮激活的潜在治疗策略！

DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) are short non-coding RNAs that control gene expression predominantly through post- transcriptional repression, implicated in the control of multiple physiological and pathological processes. Recently, we described roles for endothelial miRNAs in central aspects of vascular biology such as angiogenesis and inflammation, processes that require the coordination of numerous and complex signaling pathways in which endothelial cells (ECs) act as both active participants and regulators. Endothelial activation is essential for many vascular processes leading to inflammation, vascular remodeling and vessel growth. Cytokines, such as vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF) mediate this activation and play fundamental roles in the control of angiogenic and inflammatory responses, respectively. miRNA function is modulated by extracellular factors affecting their biogenesis or activity, thereby fine-tuning the regulation of biological responses. However, our understanding of the mechanisms governing the regulation of microRNA in ECs is limited. We postulate that physiological levels of miRNAs are regulated under conditions, such as inflammation or angiogenic activation, to coordinate specific gene expression programs in ECs. We propose three aims: Aim 1: To identify the molecular mechanisms whereby VEGF and TNF regulate miRNA levels in ECs. Aim 2: To examine the regulation of EC targets and functions by VEGF and TNF-regulated miRNA in vitro. Aim 3: To define the roles of VEGF and TNF- regulated miRNAs in vivo. In summary, completion of these aims will provide critical insight into fundamental regulatory mechanisms controlling endothelial miRNA biogenesis and activity and their impact on EC biology. Understanding the complex network involving EC miRNAs and their targets, leading to a coordinate pattern of gene expression undoubtedly will contribute to a better understanding of the cellular and molecular mechanisms that control EC activation and may identify potential therapeutic strategies for the regulation of endothelial activation through modulation of miRNA activity!