MicroRNAs in Regulation of Pulmonary Vascular Smooth Muscle Cell Proliferation

描述(申请人提供)：尽管许多基因与PAH的发病机制有关，但PAH是一种如此复杂的疾病，可能涉及多个基因。有可能这些基因受到关键调控机制的影响。MicroRNAs(MiRNAs)是一种小的非编码内源RNA分子，由大约21-25个核苷酸组成。MiRNAs通过其mRNA的3‘-非翻译区的互补序列识别其靶标，形成RNA诱导的沉默复合体，导致成熟mRNA的部分降解或翻译抑制。MiRNA途径在进化上是保守的，并调节细胞功能的许多方面，包括细胞周期、分化、增殖、生存和代谢。单个miRNAs可以调节多达数百个基因或蛋白质，使其成为PAH发病机制研究的热点。在这个方案中，我们提出了三个相互关联的目的：目的1是确定和验证在PAH患者和对照组的PASMC细胞和肺组织中miRNA的表达变化；目的2是确定miR-143在PAH患者的PASMC和肺组织中是否下调及其靶点的表达；以及目标3是确定miR-17~92簇在PAH患者的PASMC和肺组织中是否下调及其靶点的上调。 公共卫生相关性：人类的肺动脉高压是一种毁灭性的疾病，目前还没有治愈的方法。更好地了解所涉及的机制应该有助于我们改进对这种疾病的治疗和预防。微型RNA是控制几个基因表达的小分子。通过研究这些microRNAs在病变肺和对照肺中的表达，我们希望找出参与人类肺动脉高压发病机制的关键microRNAs。拟议研究的完成将为PAH的病理生理学提供新的见解，这可能导致设计治疗这种疾病的新策略。(摘要结束)

DESCRIPTION (provided by applicant): Although many genes have been implicated in the pathogenesis of PAH, PAH is such a complex disease that there are probably multiple genes involved. It is possible that these genes are under the influence of key regulatory mechanisms. MicroRNAs (miRNAs) are small non-coding endogenous RNA molecules consisting of approximately 21-25 nt. miRNAs recognize their targets through complementary sequences in their 3'-untranslated regions (UTR) of their mRNA and form RNA-induced silencing complexes, leading to the partial degradation of mature mRNA or translation repression. miRNA pathways are evolutionarily conserved and regulate many aspects of cell functions including cell cycle, differentiation, proliferation, survival, and metabolism. Single miRNAs can regulate up to hundreds of genes or proteins, making them attractive targets for study in the pathogenesis of PAH. In this proposal, we propose three interrelated aims: Aim 1 is to determine and validate changes in miRNA expression in pulmonary arterial smooth muscle (PASMC) cells and lung tissue from PAH and control subjects; Aim 2 is to determine whether miR-143 is downregulated and the expression of its targets is altered in PASMC and lung tissues of PAH patients; and Aim 3 is to determine whether miR-17~92 cluster is downregulated and their targets are upregulated in PASMC and lung tissue of PAH patients. PUBLIC HEALTH RELEVANCE: Pulmonary hypertension in humans is a devastating disease and there is no cure. A better understanding of the mechanisms involved should help us get to improved treatment and prevention of this disease. Micro RNAs are small molecules that control the expression of several genes. By studying the expression of these microRNAs in diseased and control human lungs, we hope to identify key microRNAs that are involved in the pathogenesis of pulmonary hypertension in humans. Completion of the proposed studies will provide novel insights into the pathophysiology of PAH, which may result in the design of novel strategies for the treatment of patients with this disease. (End of Abstract)