Post-transcriptional gene regulation in Alzheimer's Disease

阿尔茨海默病的转录后基因调控

• 批准号: 8335871
• 负责人: Myriam Gorospe
• 金额: $ 48.88万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8335871
• 关键词: Affect; Alleles; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Cell Cycle; Cell Death; Cell Differentiation process; Cells; Chromosomes, Human, Pair 12; Cues; DNA Repair; Disease susceptibility; Funding; Gene Expression; Gene Expression Regulation; Genes; Genetic Polymorphism; Goals; Late Onset Alzheimer Disease; Link; Mammalian Cell; Maps; Messenger RNA; MicroRNAs; Molecular Biology; Nature; Neurons; Pathogenesis; Pattern; Physiological; Post-Transcriptional Regulation; Process; Proteins; RNA; RNA Splicing; RNA-Binding Proteins; Regulation; Susceptibility Gene; Transcript; Translations; Ursidae Family; interest; oxidized LDL receptors; programs; protein expression; structural biology; transcription factor; transcription factor CP2

Mammalian cells respond to physiological and pathological cues by implementing changes in gene expression patterns. Post-transcriptional processes (RNA splicing and maturation, as well as mRNA transport, stability and translation) are increasingly recognized as being critically responsible for controlling gene expression. Two studies are underway in the RNA Regulation Section to investigate post-transcriptional gene control in Alzheimers Disease (AD). Through these studies, we seek to elucidate the contribution of mRNA sequences, RNA-binding proteins, and microRNAs towards regulating the expression of critical gene products in AD pathogenesis. During the past funding period, we have identified several RNA-binding proteins (RBPs) that associate with the APP, and have studied their influence on the expression of APP and the subcellular localization of the mRNA (Lee et al., Nature Structural & Molecular Biology, 2010). We also identified several microRNAS that affect neuronal function, including miR-375 (Abdelmohsen et al., Mol. Cell. Biol., 2010), and collaborated in studies linking neuronal DNA repair with cell cycle distribution (Tomashevski et al., Cell Death and Differentiation, 2010). Ongoing studies are assessing the regulation of APP expression by other RNA-binding proteins that recognize AU-rich transcripts. We also plan to investigate the influence of polymorphic noncoding sequences on the post-transcriptional regulation of AD susceptibility genes. The pathogenesis of late-onset AD is not well understood, but linkage studies have mapped critical late-onset AD susceptibility genes to a region in chromosome 12. Two genes in this chromosomal region have been postulated to participate in AD: oxidized LDL-receptor 1 (OLR1) and transcription factor LBP-1c/CP2/LSF. Given that these two genes bear 3UTR polymorphisms, we are investigating if such alleles with polymorphic untranslated sequences are subject to differential post-transcriptional regulation.

哺乳动物细胞通过实施基因表达模式的变化来应对生理和病理线索。 转录后过程（RNA剪接和成熟以及mRNA转运，稳定性和翻译）越来越被认为是控制基因表达的严重责任。 RNA调节部分正在进行两项研究，以研究阿尔茨海默氏病（AD）中的转录后基因控制。 通过这些研究，我们试图阐明mRNA序列，RNA结合蛋白和microRNAS对调节临界基因产物在AD发病机理中的表达的贡献。 在过去的资金期间，我们确定了与该应用程序相关联的几种RNA结合蛋白（RBP），并研究了它们对APP表达和mRNA的亚细胞定位的影响（Lee等人，自然结构和分子生物学，2010年）。 我们还确定了几种影响神经元功能的microRNA，包括miR-375（Abdelmohsen等人，Mol。Cell。Biol。，2010），并在将神经元DNA修复与细胞周期分布联系起来的研究中（Tomashevski等人，Cell and Death and Dinieation，2010年）。 正在进行的研究正在评估其他RNA结合蛋白识别富含AU的转录本的调节。 我们还计划研究多态非编码序列对AD易感基因转录后调节的影响。 晚期AD的发病机理尚不清楚，但是连锁研究已将关键的后期AD易感基因映射到12号染色体的一个区域。该染色体区域中的两个基因已被假定参与AD：氧化的LDL-LDL-RECEPTOR 1（OLR1）和转录因子LBP-1C/CP2/CP2/LSF。 鉴于这两个基因带有3UTR多态性，我们正在研究是否具有多态性未翻译序列的等位基因受到转录后调节的差异。