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（由申请人提供）：人体中的许多细胞都是静止的；也就是说，他们已经暂时停止分裂，但在情况必须生长或必须修复损坏的组织时，可以保留划分的能力。尽管静止是许多体细胞（包括干细胞）的常见状态，但我们对细胞静止的调节，细胞在静止时发生的变化以及体内的静止状况知之甚少。我们证明了静止是一种活跃而不断发展的状态，其特征是基因表达模式的广泛变化。我们假设microRNA参与调节静止观察到的大量基因表达变化。我们通过静止确定了上调和下调的特定microRNA。 miR-31被静止下调，并在结肠和胰腺癌（尤其是晚期肿瘤）中上调。我们已经表明，miR-31的过表达导致静止的速度更快，更健壮的细胞周期进入。我们在这里建议识别miR-31靶标并定义影响静止的机制。我们还建议定义MiR-31启动子内部序列中其下调下调的序列。只有少数分子可以从静止中加速细胞周期的进入，包括MYC，E2F和CyclinE。我们预计，阐明miR-31促进增殖的机制将阐明重要的新信号通路。公共卫生相关性：许多常见疾病可能是由于静止失败而导致的；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关键属性，其下降可能导致衰老。我们在这里提出要表征静止中心的一个特定信号通路的作用，并期望所鉴定的机制将为广泛的医疗条件提供重要的见解。