MicroRNAs in Endothelial Cell Activation.

描述（由申请人提供）：MicroRNA (miRNA) 是短非编码 RNA，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 miRNA 在血管生物学的核心方面的作用，例如血管生成和炎症，这些过程需要协调众多复杂的信号通路，其中内皮细胞 (EC) 既充当积极的参与者又充当调节者。内皮激活对于导致炎症、血管重塑和血管生长的许多血管过程至关重要。细胞因子，例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 的功能受到影响其生物发生或活性的细胞外因素的调节，从而微调生物反应的调节。然而，我们对 EC 中 microRNA 调节机制的了解有限。我们假设 miRNA 的生理水平在炎症或血管生成激活等条件下受到调节，以协调 EC 中的特定基因表达程序。我们提出三个目标： 目标 1：确定 VEGF 和 TNF 调节 EC 中 miRNA 水平的分子机制。目标 2：体外检查 VEGF 和 TNF 调节的 miRNA 对 EC 靶点和功能的调节。目标 3：确定 VEGF 和 TNF 调节的 miRNA 在体内的作用。总之，这些目标的完成将为控制内皮 miRNA 生物合成和活性及其对 EC 生物学的影响的基本调控机制提供重要的见解。了解涉及 EC miRNA 及其靶标的复杂网络，从而形成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，并可能确定通过调节 miRNA 活性来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!