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miRNA Regulation of Aquaporin 1 Modulates Vascular Remodelling during Cirrhosis

水通道蛋白 1 的 miRNA 调控可调节肝硬化期间的血管重塑

基本信息

批准号：
9324216
负责人：
Robert Christian Huebert
金额：
$ 16.91万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-13 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9324216
关键词：
3-Dimensional AQP1 gene Address Attenuated Binding Sites Bulla Cell Volumes Cells Cicatrix Cirrhosis Data Endothelial Cells Expenditure Extracellular Matrix Fibrosis Foundations Healthcare In Vitro Injury Knockout Mice Liver Liver Cirrhosis Liver Fibrosis Membrane Messenger RNA Methods MicroRNAs Modeling Molecular Morbidity - disease rate Osmolalities Pathologic Neovascularization Phenotype Portal Hypertension Process Promoter Regions Proteins Regulation Shapes Sleeping Beauty System Techniques Testing Translations Untranslated RNA Vascular remodeling Work angiogenesis base blood vessel development chronic liver disease enhancer binding protein imaging approach in vivo mRNA Transcript Degradation mortality mouse model nanoencapsulated novel overexpression public health relevance targeted treatment therapeutic target transcription factor water channel

项目摘要

DESCRIPTION (provided by applicant): Cirrhosis and portal hypertension are the cause of significant morbidity, mortality, and healthcare expenditures. Since hepatic fibrosis and pathological angiogenesis are processes that are mutually dependent and since liver endothelial cell (LEC) invasion is a requisite step for angiogenesis, studies of the detailed molecular mechanisms governing LEC invasion are of great importance. LEC invasion is modulated by mechanisms involving localized cell volume regulation and osmotically driven membrane shape changes. Aquaporin-1 (AQP1) is an integral membrane water channel that is dramatically overexpressed in LEC during cirrhosis and facilitates invasion through the cirrhotic microenvironment. The precise mechanisms responsible for the overexpression of AQP1 in LEC during cirrhosis remain largely uninvestigated. Based on selected background rationale and novel preliminary data, we propose the central hypothesis that local osmotic fluctuation during cirrhosis drives AQP1 overexpression by altering levels of the osmotically sensitive, AQP1 regulatory miRNAs, miR-666 and miR-708, thereby promoting dynamic membrane blebbing, LEC invasion, and angiogenesis during cirrhosis. To accomplish our overall objective, we will employ complementary molecular, cell biologic, an in vivo approaches to establish the mechanism of AQP1 overexpression and the effect of AQP1 regulatory miRNAs on LEC invasion, angiogenesis, and cirrhosis. Aim I will focus on how local osmolality silences miR- 666 and miR-708 to subsequently increase AQP1 in LEC. Aim II investigates the effects of miR-666 and miR- 708 on the angiogenic phenotype of LEC. Aim III tests the effects of miR-666 and miR-708 overexpression on angiogenesis and fibrosis in vivo. The results will mechanistically extend the preliminary findings and provide novel information regarding the osmotically sensitive, miRNA-based mechanisms, controlling AQP1 overexpression and may ultimately produce the foundation for anti-angiogenic therapies targeting AQP1 and its molecular regulators in cirrhosis.

描述（由申请人提供）：肝硬化和门静脉高压是导致显着发病率、死亡率和医疗支出的原因。由于肝纤维化和病理性血管生成是相互依赖的过程，并且肝内皮细胞（LEC）侵袭是血管生成的必要步骤，因此研究控制LEC侵袭的详细分子机制非常重要。 LEC 侵袭通过涉及局部细胞体积调节和渗透压驱动的膜形状变化的机制来调节。 Aquaporin-1 (AQP1) 是一种完整的膜水通道，在肝硬化期间在 LEC 中显着过度表达，并促进通过肝硬化微环境的侵袭。肝硬化期间 LEC 中 AQP1 过度表达的确切机制在很大程度上仍未得到研究。基于选定的背景原理和新的初步数据，我们提出了中心假设，即肝硬化期间的局部渗透压波动通过改变渗透敏感的 AQP1 调节 miRNA、miR-666 和 miR-708 的水平来驱动 AQP1 过度表达，从而促进肝硬化期间的动态膜起泡、LEC 侵袭和血管生成。为了实现我们的总体目标，我们将采用互补的分子、细胞生物学、体内方法来建立 AQP1 过表达的机制以及 AQP1 调节 miRNA 对 LEC 侵袭、血管生成和肝硬化的影响。目标我将重点关注局部渗透压如何沉默 miR-666 和 miR-708，从而随后增加 LEC 中的 AQP1。 Aim II 研究 miR-666 和 miR-708 对 LEC 血管生成表型的影响。 Aim III 测试 miR-666 和 miR-708 过表达对体内血管生成和纤维化的影响。这些结果将在机制上扩展初步发现，并提供有关渗透敏感、基于 miRNA 的机制、控制 AQP1 过度表达的新信息，并可能最终为肝硬化中针对 AQP1 及其分子调节因子的抗血管生成疗法奠定基础。