Role of microRNAs in T cell development

microRNA 在 T 细胞发育中的作用

• 批准号: 8349336
• 负责人: Alfred Singer
• 金额: $ 39.09万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/8349336
• 关键词: Apoptosis; Apoptotic; Development; Dicer Enzyme; Equilibrium; Eukaryota; Functional RNA; Gene Expression; Generations; Genes; Goals; Knock-out; Messenger RNA; MicroRNAs; Mus; Post-Transcriptional Regulation; Protein Biosynthesis; RNA; RNA Interference; Role; Staging; T-Cell Development; T-Lymphocyte; Thymocyte Development; Thymus Gland; human DICER1 protein; protein expression; thymocyte

RNA intererence is a one of the major mechanisms of post-transcriptional regulation of protein expression in eukaryotes. This mechanism is using small non-coding RNAs (miRNAs) to destabilize specific mRNAs and to suppress protein synthesis. Many miRNAs genes are expressed in T cells during development in a thymus. However the function of RNAi in T cell development remains unclear. To investigate the role of RNAi during thymic development we generated conditional knockout of the enzyme Dicer in the mouse, which is critical for miRNA generation. We observed a dramatic reduction in the number of thymocytes in Dicer-deficient mice and we determined that the reason is a block of progression from DN to DP stage during thymocyte development. Importantly, we found an alteration in the balance between pro- and anti-apoptotic factors in RNAi deficient DP thymocytes. We also observed that RNAi-deficient thymocytes are rapidly undergoing apoptosis. Most importantly, we have also identified the precise gene whose expression is downregulated by microRNAs to permit survival of developing T cells in the thymus.

RNA干扰是真核生物蛋白质表达转录后调控的主要机制之一。这种机制是使用小的非编码RNA（miRNA）来破坏特定mRNA的稳定性并抑制蛋白质合成。许多miRNA基因在胸腺发育期间在T细胞中表达。然而，RNAi在T细胞发育中的功能仍不清楚。为了研究RNAi在胸腺发育过程中的作用，我们在小鼠中产生了对miRNA产生至关重要的酶Dicer的条件性敲除。我们观察到Dicer缺陷小鼠的胸腺细胞数量急剧减少，我们确定其原因是胸腺细胞发育期间从DN到DP阶段的进展受阻。重要的是，我们发现了RNAi缺陷DP胸腺细胞中促凋亡因子和抗凋亡因子之间平衡的改变。我们还观察到RNAi缺陷的胸腺细胞正在迅速发生凋亡。最重要的是，我们还确定了精确的基因，其表达被microRNA下调，以允许发育中的T细胞在胸腺中存活。