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

• 批准号: 8609198
• 负责人: Robert Christian Huebert
• 金额: $ 14.7万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-13 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8609198
• 关键词: 3-Dimensional; AQP1 gene; Address; Attenuated; Binding Sites; Blood Vessels; Bulla; Cell Volumes; Cells; Cicatrix; Cirrhosis; Data; Development; Endothelial Cells; Expenditure; Extracellular Matrix; Fibrosis; Foundations; Functional RNA; Healthcare; Image; 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; Vascular remodeling; Work; angiogenesis; base; chronic liver disease; enhancer binding protein; in vivo; mRNA Transcript Degradation; mortality; mouse model; nanoencapsulated; novel; overexpression; public health relevance; therapeutic target; transcription factor; water channel

PROJECT SUMMARY/ABSTRACT 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.

项目总结/摘要 肝硬化和门静脉高压症是导致显著发病率、死亡率和医疗费用的原因。 由于肝纤维化和病理性血管生成是相互依赖的过程， 内皮细胞（LEC）侵袭是血管生成的必要步骤，详细的分子生物学研究表明， 控制LEC入侵的机制非常重要。LEC的侵袭受到多种机制的调节 涉及局部细胞体积调节和免疫驱动的膜形状变化。水通道蛋白-1 （AQP 1）是一个完整的膜水通道，在肝硬化期间在LEC中显著过表达， 促进通过微环境的侵入。造成这种情况的确切机制 在肝硬化期间LEC中AQP 1过表达仍在很大程度上未被研究。根据选定的背景 基本原理和新的初步数据，我们提出了中心假设， 肝硬化通过改变血管敏感性AQP 1调节性miRNA的水平来驱动AQP 1过表达， miR-666和miR-708，从而促进动态膜起泡、LEC侵袭和血管生成 在肝硬化期间。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， 建立AQP 1过表达的机制和AQP 1调节的作用的体内方法， miRNA对LEC侵袭、血管生成和肝硬化的影响。目的我将重点关注局部渗透压是如何沉默miR- 666和miR-708随后增加LEC中的AQP 1。目的II研究miR-666和miR-106对细胞凋亡的影响。 708对LEC血管生成表型的影响。目的III检测miR-666和miR-708过表达对人乳腺癌细胞系的影响。 血管生成和纤维化。这些结果将在机械上扩展初步结果，并提供 新的信息，关于敏感的，基于miRNA的机制，控制AQP 1 可能最终为靶向AQP 1的抗血管生成治疗奠定基础， 肝硬化中的分子调节因子。