Mechanisms of MicroRNA-Mediated Regulation of Cellular Proliferation in Vascular Malformations

点击翻译按钮获取中文摘要

Summary Vascular malformations are a family of congenital anomalies that are classified by the vessel type affected: lymphatic (LM), venous (VM), arteriovenous (AVM), and capillary (CM) malformations. These lesions vary in size and location and can result in significant or life-threatening morbidity due to infiltration and compression of critical structures. Several somatic, gain-of-function mutations have been identified in vascular malformation endothelial cells, which are thought to drive aberrant cell proliferation by activating the PIK3/AKT/mTOR and RAS/ERK signaling cascades. MicroRNAs (miRNAs) act as post-transcriptional regulators of gene expression and are necessary for vascular and lymphatic endothelial cell growth and development; however, their functions in vascular malformations are unknown. We have demonstrated that miR-21 is upregulated in LMs, which results in increased proliferation of LM endothelial cells. In support, miR-21 is associated with hyper-phosphorylation of MAPK, resulting in a hyperproliferative phenotype. In accordance, we hypothesize that alterations in miRNA expression in vascular malformation endothelial cells drive their proliferation by facilitating the activation of pro- growth signaling cascades. Our long-term goal is to identify suitable miRNA targets for the development of deliverable, miRNA-based therapeutics. This proposal aims to determine which miRNAs are differentially expressed between affected and normal tissue, identify the mRNA targets of these miRNAs, identify the functional proteins, and demonstrate the effects of this differential expression. We will test our hypotheses with the following Specific Aims: (1) Establish the miRNA expression profile of vascular malformations and (2) Determine the effects of aberrant miRNA expression on vascular and lymphatic endothelial cell signaling cascades and cellular phenotype.