Mechanisms of microRNA-mediated regulation of cellular proliferation in vascular malformations

血管畸形是淋巴或血管内皮系统的先天性异常，其特征是内皮细胞的超增殖表型，导致扩张静脉、动脉和淋巴通道的形成。由于这些病变容易扩大、侵犯附近解剖结构、出血、感染、引起明显的疼痛和毁容以及转移重要器官的血液供应，因此可引起严重的发病率。这些病变的治疗传统上依赖于手术切除或硬化疗法，这有很高的复发率和并发症。在这些病变的内皮细胞中，一些控制增殖的基因的体细胞、功能获得性突变已被证实，这使得这些基因及其下游信号级联成为分子药物治疗的有吸引力的靶点。在初步实验中，我们已经确定了microRNA-21 (miR-21)，一种已知的内皮细胞增殖调节剂，在淋巴畸形组织中上调，导致MAPK的过度磷酸化和细胞生长增加。在本提案中，我们将确定血管畸形组织和内皮细胞的整个miRNA表达谱，以识别所有异常表达的miRNA并确定

Vascular malformations are congenital anomalies of the lymphatic or vascular endothelial system and are characterized by a hyperproliferative phenotype of endothelial cells, which leads to the formation of ectatic veins, arteries, and lymphatic channels. These lesions can cause significant morbidity due to their propensity to enlarge, encroach on nearby anatomical structures, hemorrhage, become infected, cause significant pain and disfigurement, and divert blood supply from vital organs. Treatments for these lesions has traditionally relied on surgical excision or sclerotherapy, which have high rates of recurrence and complications. Several somatic, gain-of-function mutations in genes which control proliferation have been implicated in the endothelium of these lesions, making these genes and their downstream signaling cascades attractive targets for molecular pharmacotherapies. In preliminary experiments, we have identified microRNA-21 (miR-21), a known regulator of endothelial cell proliferation, as upregulated in lymphatic malformation tissue, leading to hyperphosphorylation of MAPK and increased cell growth. In this proposal, we will determine the entire miRNA expression profile of vascular malformation tissue and endothelial cells to identify all aberrantly expressed miRNAs and determine their effects on cellular proliferation and abnormal vessel formation. We will utilize previously collected frozen tissue specimens, freshly harvested vascular anomaly tissue and isolated endothelial cells, and existing normal endothelial cell lines which will undergo miRNA sequencing, proteomics analysis, and in vitro and in vivo growth assays. The long term goals are to identify potential miRNA-based treatments which target vascular anomaly endothelial proliferation and identify circulating biomarkers of vascular anomalies which are useful for diagnostics and treatment monitoring.