RNA METABOLISM DURING CELLULAR SENESCENCE

描述(改编自应用程序)：的一个重要特征 细胞衰老是细胞增殖能力的丧失，在此期间 细胞表现出形态变化和基因表达的变化。 真核细胞中的基因表达在很大程度上受 Pre-mRNA的转录后修饰，包括 多聚腺苷酸化、切割和选择性剪接。尽管后- 转录过程已经在其他系统中进行了研究，其 细胞老化的相关性还没有被研究过。这位调查员已经 发现了蛋白质水平和活性的变化， 与衰老成纤维细胞中的异质核RNA(HnRNA)结合； 这些是hnRNP A1和A2蛋白。这两种功能在 成熟基因的生物发生和稳定性。此外，增加了 两种新的RNA结合蛋白(LPA-38和LPA-45)的活性 在衰老的成纤维细胞中被发现；这些是hnRNP A1和A2 蛋白质。两者都是两种新的活性增强的RNA结合 蛋白质(LPA-38和LPA-45)在衰老过程中被发现 成纤维细胞。这项研究的假设是，后遗症的改变- 转录过程在影响基因方面起着重要作用 在细胞衰老过程中的表达。 这项提案的目标是调查与年龄相关的角色 特定的RNA结合蛋白。转录后的变化 衰老细胞中的处理将通过使用RNA结合和 拼接分析。将评估寿命是否将是 通过调控hnRNP A1和A2蛋白的表达而改变 使用可诱导逆转录病毒系统的正常人成纤维细胞。基于 初步发现，预计寿命将为 加长了。对寿命的影响可能是hnRNP A1和 A2调节特定RNA物种的表达。随后， 研究人员将通过使用差异来识别这些RNA 展示。其次，LPA-38和LPA-45的基因，可能是推定的 负增长，监管者，将被孤立和定性。一次 他们的cDNA已经被克隆和测序，功能分析将是 进行TP以确定细胞衰老过程中的相关性。被更改的 RNA结合蛋白(hnRNP A1和A2，LPA-38和45)的活性为 预计会对特定的RNA产生几种影响，如减少 信使核糖核酸，有缺陷的蛋白质和低效的翻译。都是有潜力的 诱导细胞衰老的机制。中国的长期目标是 在本申请中概述的研究是为了表征基因 通过差异显示识别并评估后的贡献- 转录加工在调节衰老相关基因中的作用 表情。

Description (Adapted from Application): A significant characteristic of cellular senescence is the loss of proliferative capacity, during which cells exhibit morphological changes and alterations in gene expression. Gene expression in eukaryotic cells is regulated to a large extent by post-transcriptional modifications of pre-mRNA, which includes polyadenylation, cleavage, and alternative splicing. Although post- transcriptional process has been investigated in other systems, its relevance in cellular aging has not been examined. This investigator has identified alterations in the levels and activities of proteins that bind to heterogeneous nuclear RNA (hnRNA) in senescent fibroblasts; these are the hnRNP A1 and A2 proteins. Both are functional in the biogenesis and stability of mature mRNA. In addition, increased activities of two novel RNA-binding proteins (LPA-38 and LPA-45) have been uncovered in senescent fibroblasts; these are the hnRNP A1 and A2 proteins. Both are increased activities of two novel RNA-binding proteins (LPA-38 and LPA-45) have been uncovered in senescent fibroblasts. The hypothesis for this study is that alterations in post- transcriptional processing have an important role in affecting gene expression during cellular senescence. The goals of this proposal are to investigate the age-related roles of specific RNA-binding proteins. Changes in post-transcriptional processing in senescent cells will be assessed by using RNA binding and splicing assays. Assessment will be made of whether lifespan will be altered by manipulating the expression of hnRNP A1 and A2 proteins in normal human fibroblasts using an inducible retroviral system. Based on preliminary findings, it is anticipated that lifespan will be lengthened. The effects on lifespan would be the result of hnRNP A1 and A2 modulating the expression of specific RNA species. Subsequently the investigator will seek to identify these RNAs by the use of differential display. Secondly, the genes for LPA-38 and 45, which may be putative negative growth, regulators, will be isolated and characterized. Once their cDNAs have been cloned and sequenced, functional assays will be performed tp determine relevance during cellular senescence. The altered activities of RNA-binding proteins (hnRNP A1 and A2, LPA-38 and 45) are expected to produce several effects for specific RNAs, such as reduced mRNA, defective proteins, and inefficient translation. All are potential mechanisms to induce cellular senescence. The long-term goals of the studies outlined in this application are to characterize the genes identified by differential display and to assess the contribution post- transcriptional processing has in modulating senescence-related gene expression.