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

MicroRNA介导的血管畸形细胞增殖调节机制

基本信息

批准号：
10669303
负责人：
GRAHAM M STRUB
金额：
$ 30.24万
依托单位：
ARKANSAS CHILDREN'S HOSPITAL RES INST
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-11 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669303
关键词：
Affect Biological Assay Blood Vessels Blood capillaries Cell Line Cell Proliferation Cells Centers of Research Excellence Childhood Classification Development Disease Doctor of Medicine Doctor of Philosophy Endothelial Cells FRAP1 gene Family Gene Expression Goals Growth Growth and Development function Harvest Human Individual Infiltration Lesion Life Location Lymphatic Lymphatic Endothelial Cells Lymphoid Tissue MAP Kinase Gene Mediating Messenger RNA MicroRNAs Morbidity - disease rate Multiomic Data Normal tissue morphology PIK3CG gene Pediatric Research Phenotype Population Proliferating Proteins Proto-Oncogene Proteins c-akt Regulation Regulator Genes Research Project Grants Resources Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Structure Testing Therapeutic Tissues Transfection Up-Regulation Vascular Endothelial Cell Vascular Endothelium Venous Western Blotting angiogenesis cell growth cell growth regulation congenital anomaly data integration differential expression epigenomics gain of function mutation inhibitor malformation multiple omics new therapeutic target phosphoproteomics posttranscriptional proteogenomics therapeutic miRNA therapeutic target transcriptome sequencing

项目摘要

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.

总结