The Role of MicroRNAs in Cellular Quiescence

MicroRNA 在细胞静止中的作用

• 批准号: 7644461
• 负责人: Hilary A Coller
• 金额: $ 28.05万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7644461
• 关键词: Affect; Aging; Biological Assay; Cell Cycle; Cell Cycle Regulation; Cells; Characteristics; Colorectal; Colorectal Neoplasms; Cyclin E; Development; Diagnostic Neoplasm Staging; Disease; Down-Regulation; Electrophoretic Mobility Shift Assay; Elements; Failure; Fibroblasts; Fibrosis; Flow Cytometry; Functional RNA; Gene Expression; Genes; Human body; Individual; Laboratories; Length; Luciferases; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Medical; MicroRNAs; Microarray Analysis; Molecular; Monitor; Mutate; Organism; Pattern; Phenotype; Plasmids; Proliferating; Promoter Regions; Regulatory Element; Reporter; Research; Role; Series; Signal Pathway; Simulate; Somatic Cell; Stem cells; Testing; Tissues; Transcript; Transfection; Tumor stage; Ulcer; base; c-myc Genes; cell growth regulation; insight; knock-down; migration; overexpression; pancreatic neoplasm; programs; promoter; public health relevance; repaired; tumor; tumor initiation; tumorigenesis; vector

DESCRIPTION (provided by applicant): Many cells in the human body are quiescent; that is, they have temporarily stopped dividing but retain the capacity to divide when conditions are suitable, for instance, when the organism must grow or a damaged tissue must be repaired. Although quiescence is a common state for many somatic cells, including stem cells, we know remarkably little about the regulation of cellular quiescence, the changes that cells undergo upon becoming quiescent, and what quiescence looks like in the body. We demonstrated that quiescence is an active and evolving state characterized by extensive changes in gene expression patterns. We hypothesized that microRNAs are involved in regulating the large number of gene expression changes observed with quiescence. We identified specific microRNAs up- and down-regulated with quiescence. miR-31 is downregulated with quiescence and is upregulated in colon and pancreatic cancer, especially late stage tumors. We have shown that overexpression of miR-31 results in a faster and more robust cell cycle entry from quiescence. We propose here to identify miR-31 targets and define the mechanisms by which it affects quiescence. We also propose to define the sequences within the miR-31 promoter responsible for its downregulation with quiescence. Only a small number of molecules can hasten cell cycle entry from quiescence, including myc, E2F and cyclin E. We anticipate that elucidating the mechanisms by which miR-31 promotes proliferation will elucidate an important new signaling pathway. PUBLIC HEALTH RELEVANCE: Many common diseases likely result from failures of quiescence; that is, an inability of cells to temporarily stop dividing. These include developmental abnormalities, tumors, fibrosis, and ulcers. The ability to reenter the cell cycle after quiescence is a critical attribute of stem cells, and its decline likely contributes to aging. We propose here to characterize the role of one specific signaling pathway central to quiescence, and expect that the mechanisms identified will provide important insights into a wide range of medical conditions.

描述（申请人提供）：人体内的许多细胞是静止的；也就是说，它们暂时停止分裂，但在条件合适时保留分裂的能力，例如，当生物体必须生长或受损的组织必须修复时。尽管静止是包括干细胞在内的许多体细胞的常见状态，但我们对细胞静止的调节、细胞静止后所经历的变化以及静止在体内是什么样子知之甚少。我们证明，静止是一种活跃的、不断演化的状态，其特征是基因表达模式的广泛变化。我们假设 microRNA 参与调节在静止状态下观察到的大量基因表达变化。我们鉴定了在静止状态下上调和下调的特定 microRNA。 miR-31 在静止状态下下调，在结肠癌和胰腺癌，尤其是晚期肿瘤中上调。我们已经证明，miR-31 的过度表达会导致细胞从静止状态更快、更稳健地进入细胞周期。我们在此建议确定 miR-31 靶标并定义其影响静止的机制。我们还建议定义 miR-31 启动子内负责其静态下调的序列。只有少数分子可以加速细胞周期从静止状态进入，包括 myc、E2F 和细胞周期蛋白 E。我们预计，阐明 miR-31 促进增殖的机制将阐明一个重要的新信号通路。公共卫生相关性：许多常见疾病可能是由于静息失败造成的。也就是说，细胞无法暂时停止分裂。这些包括发育异常、肿瘤、纤维化和溃疡。静止后重新进入细胞周期的能力是干细胞的一个关键属性，其衰退可能会导致衰老。我们在此建议描述一种对静止至关重要的特定信号通路的作用，并期望所确定的机制将为广泛的医疗状况提供重要的见解。