MicroRNAs in Regulation of Pulmonary Vascular Smooth Muscle Cell Proliferation

MicroRNA 调控肺血管平滑肌细胞增殖

• 批准号: 8211933
• 负责人: J. Usha RAJ
• 金额: $ 7.96万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-23 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8211933
• 关键词: 3' Untranslated Regions; Cell Cycle; Cell physiology; Cessation of life; Complex; Disease; Down-Regulation; Endothelial Cells; Failure; Fibroblasts; Functional RNA; Functional disorder; Genes; Human; Hypertension; Lung; Messenger RNA; Metabolism; MicroRNAs; Molecular; Molecular Profiling; Pathogenesis; Pathway interactions; Patients; Proteins; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; RNA; RNA-Induced Silencing Complex; Regulation; Repression; Signal Pathway; Smooth Muscle; Smooth Muscle Myocytes; Structure of parenchyma of lung; Translations; Validation; Vascular remodeling; Ventricular; abstracting; design; disorder prevention; hypertension control; improved; insight; migration; novel; novel strategies; research study; small molecule; vascular smooth muscle cell proliferation

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)

描述（申请人提供）：虽然PAH的发病机制涉及许多基因，但PAH是一种复杂的疾病，可能涉及多个基因。这些基因可能受到关键调控机制的影响。 MicroRNA (miRNA) 是由大约 21-25 nt 组成的小型非编码内源 RNA 分子。 miRNA 通过 mRNA 3' 非翻译区 (UTR) 中的互补序列识别其靶标，并形成 RNA 诱导的沉默复合物，导致成熟 mRNA 的部分降解或翻译抑制。 miRNA 通路在进化上是保守的，并调节细胞功能的许多方面，包括细胞周期、分化、增殖、存活和代谢。单个 miRNA 可以调节多达数百个基因或蛋白质，使其成为 PAH 发病机制研究的有吸引力的靶标。在本提案中，我们提出了三个相互关联的目标： 目标 1 是确定和验证 PAH 和对照受试者的肺动脉平滑肌 (PASMC) 细胞和肺组织中 miRNA 表达的变化；目标2是确定PAH患者的PASMC和肺组织中miR-143是否下调以及其靶标的表达是否发生改变；目的3是确定PAH患者的PASMC和肺组织中miR-17~92簇是否下调且其靶标是否上调。 公共卫生相关性：人类肺动脉高压是一种毁灭性的疾病，无法治愈。更好地了解所涉及的机制应该有助于我们改进这种疾病的治疗和预防。 Micro RNA 是控制多个基因表达的小分子。通过研究这些 microRNA 在患病和对照人肺中的表达，我们希望鉴定出参与人类肺动脉高压发病机制的关键 microRNA。完成拟议的研究将为 PAH 的病理生理学提供新的见解，这可能会导致设计治疗该疾病患者的新策略。 （摘要完）