miRNAs and PPAR-gamma-induced neuroprotection

描述（由申请人提供）：miRNA通过RNA聚合酶II从独立的miRNA基因或从蛋白质编码基因的内含子转录为初级miRNA（miR）。已知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。我们做了一个在电脑观察，某些小RNA的启动子含有转录因子过氧化物酶体增殖物激活受体的结合位点？称为PPRE。初步的研究表明，几个在其启动子中含有PPREs的miRNA被PPAR？激动剂罗格列酮表明，PPAR？可能控制的miRNA的表达。除了靶向mRNA的3 '-UTR以抑制翻译之外，miRNA还可以以序列特异性方式结合蛋白质编码基因的启动子。利用生物信息学技术，我们观察到了4个小RNA在PPAR？启动子表明这些miRNAs可能控制过氧化物酶体增殖物激活受体？基因表达。有趣的是，PPAR？启动子包含在其启动子中具有PPRE的miRNA的结合位点。例如，mir-329和miR-145的启动子分别显示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？和特定的miRNA相互调节，在维持细胞平衡方面具有重要的后果。此外，一些多效性的神经保护作用的过氧化物酶体增殖物激活受体？激动剂可能是由于它们对miRNA的作用。目的1是检测是否有PPAR？激活改变PPRE的表达，并研究是否PPAR？下游miRNA在PPAR介导的神经保护中起作用。目的二是检测特异性miRNAs是否能诱导PPAR？通过启动子相互作用表达，以及是否可以加强由PPAR提供的神经保护？激动剂总的目标是研究，如果PPAR？与某些miRNA形成循环回路，相互诱导具有功能意义。 公共卫生相关性：转录因子和microRNA是基因和蛋白质表达的主要控制者。该建议希望评估称为PPAR的转录因子与某些miRNA在介导缺血后的神经保护中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.