miRNAs and PPAR-gamma-induced neuroprotection

描述(申请人提供)：miRNAs由RNA聚合酶II从独立的miRNA基因或蛋白质编码基因的内含子转录为初级miRNAs(PrimiR)。已知的miRNA基因启动子含有许多转录因子结合位点，但转录因子在miRNA生物发生中的作用尚不清楚。我们在电子显微镜下观察到，某些miRNAs的启动子含有转录因子PPAR？的结合位点。被称为PPRE。初步研究表明，几种启动子中含有PPRE的miRNAs可被PPAR？激动剂罗格列酮提示PPAR可能控制miRNAs的表达。除了以mRNAs的3‘-UTRs为靶点抑制翻译外，miRNAs还可以以序列特异性的方式与蛋白质编码基因的启动子结合。利用生物信息学方法，我们观察到4个miRNAs在PPAR？启动子表明这些miRNAs可能控制PPAR？基因表达。有趣的是，PPAR？启动子包含启动子中含有PPRE的miRNAs的结合位点。例如，mir-329和miR-145的启动子各有4个PPRE，而PPAR？启动子显示了miR-329和miR-145的结合位点。我们假设PPAR？特定的miRNAs相互调节，在维持细胞平衡方面产生重大影响。此外，PPAR的一些多效性神经保护作用？激动剂可能是由于它们对miRNAs的影响。目标1是测试PPAR是否？激活改变含有PPRE的miRNAs的表达，并研究PPAR？下游miRNAs在PPAR介导的神经保护中发挥作用。目的2是测试特定的miRNAs是否能诱导PPAR？通过启动子的相互作用表达，这是否可以加强PPAR提供的神经保护？激动剂。总体目标是研究PPAR？与一定的miRNA处于一个循环中，它们的相互诱导性具有功能意义。 与公共健康相关：转录因子和microRNAs是基因和蛋白质表达的主要控制者。这项建议希望评估一种称为PPAR的转录因子与某些miRNAs在介导缺血后神经保护方面的相互作用和随后的后果。

DESCRIPTION (provided by applicant): The miRNAs are transcribed as primary miRNAs (primiRs) by RNA polymerase II from either independent miRNA genes or from the introns of protein-coding genes. The miRNA gene promoters are known to contain many transcription factor binding sites, but the role of transcription factors in miRNA biogenesis is not yet understood. We made an in silico observation that the promoters of certain miRNAs contain binding sites for the transcription factor PPAR? known as PPREs. Preliminary studies showed that several miRNAs that contain PPREs in their promoters were induced by PPAR? agonist rosiglitazone indicating that PPAR¿ might control the expression of miRNAs. In addition to targeting 3'-UTRs of mRNAs to repress translation, the miRNAs can also bind to the promoters of protein-coding genes in a sequence-specific manner. With bioinformatics, we observed binding sites for 4 miRNAs in PPAR? promoter indicating that those miRNAs might control PPAR? gene expression. Interestingly, PPAR? promoter contains binding sites for miRNAs that have PPREs in their promoters. For example, promoters of mir-329 and miR-145 showed 4 PPREs each while PPAR? promoter showed binding site for both miR-329 and miR-145. We hypothesize that PPAR? and specific miRNAs modulate each other with significant consequences in maintaining cellular equilibrium. Furthermore, some of the pleiotropic neuroprotective effects of PPAR? agonists might be due to their effect on miRNAs. Aim 1 is to test if PPAR? activation alters the expression of PPRE-containing miRNAs and to study if PPAR? down-stream miRNAs play a role in PPAR-mediated neuroprotection. Aim 2 is to test if specific miRNAs can induce PPAR? expression by promoter interaction and if that can potentiate the neuroprotection afforded by PPAR? agonists. The overall goal is to study if PPAR? is in a cyclical loop with certain miRNA and their mutual inducibility has functional significance. PUBLIC HEALTH RELEVANCE: Transcription factors and microRNAs are master controllers of gene and protein expression. This proposal wishes to evaluate the mutual interaction and the subsequent consequences of a transcription factor known as PPAR with certain miRNAs in mediating neuroprotection after ischemia.