ROLE OF MIR146B IN SURVIVAL & SELF RENEWAL OF MAMMARY ALVEOLAR PROGENITOR CELLS

MIR146B 在生存中的作用

• 批准号: 8360688
• 负责人: FARIBA BEHBOD
• 金额: $ 2.95万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360688
• 关键词: Alveolar; Alveolar Cell; Biological Process; Cell Line; Cell Survival; Cells; Cessation of life; Development; Ductal; Epithelial Cells; Female; Functional RNA; Funding; Gene Expression; Genes; Genetic Translation; Genome; Goals; Grant; In Vitro; Luciferases; Malignant Neoplasms; Mammary gland; Mediating; MicroRNAs; Molecular; Molecular Target; Mus; National Center for Research Resources; Neoplasm Metastasis; Physiological; Play; Pregnancy; Principal Investigator; RNA Interference; Regulation; Regulator Genes; Reporter; Reporting; Research; Research Infrastructure; Resources; Role; Source; Stem cells; United States National Institutes of Health; Up-Regulation; cancer cell; cell motility; chromatin immunoprecipitation; cost; human disease; malignant breast neoplasm; mammary gland development; pregnant; progenitor; self-renewal; stem

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. MicroRNAs (miRNAs) are a class of endogenous, non-coding, single-stranded molecules which are crucial post-transcriptional regulators of gene expression. Traditionally the miRNA function in post-transcriptional gene silencing. An estimated 30-60% of the genome is regulated by miRNA-mediated silencing, but recent studies described that miRNA can also mediate upregulation of mRNA translation. Previous studies have shown that miRNAs participate in a wide range of biological functions and play important roles in various human diseases including cancer. While miRNAs important to most somatic stem cells have been identified, the role that miRNAs play in normal mammary gland stem and progenitor cells has yet to be fully investigated. Recently, miR146b has been reported to be involved in inhibition of cancer cell migration and invasion, and suppression of breast cancer metastasis. However, the physiological role of miR146b in normal mammary gland development has not been determined. The objective of this application is to discover the role of miR146b in the survival and self-renewal of mammary alveolar progenitor cells and identify its downstream molecular targets. Our central hypothesis is that miR146b facilitates alveolar progenitor survival and self-renewal during pregnancy through activation of Stat-5 and inhibition of Stat-3. Stat-5 plays an essential role in alveolar cell survival and self-renewal during pregnancy and Stat-3 plays a crucial role in mammary alveolar death during involution. We will achieve these experimental goals through the following specific aims: Specific aim 1: To demonstrate that miR146b promotes survival and self-renewal in mammary alveolar progenitor cells, this will be achieved by in vitro manipulation of the expression of miR146b in multipotent, ductal and alveolar progenitor cells derived from a mammary epithelial cell line and in alveolar progenitor cells derived from female Balb/C virgin and pregnant mice. Specific aim 2: Elucidate the role of miR146b in suppressing Stat-3 and activation of Stat-5. Luciferase reporter and CHIP assays will be used to confirm miR146b regulation of these two genes.The long-term goal of our research is to elucidate the role of microRNAs in mammary gland stem and progenitor cell survival and self-renewal.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 microRNA（miRNA）是一类内源性，非编码的单链分子，是至关重要的 基因表达的转录后调节剂。传统上，转录后的miRNA功能 基因沉默。估计基因组的30-60％受miRNA介导的沉默调节，但最近 研究描述，miRNA还可以介导mRNA翻译的上调。先前的研究已有 表明miRNA参与了广泛的生物学功能，并在各种中发挥重要作用 包括癌症在内的人类疾病。尽管已经确定了对大多数体细胞细胞重要的miRNA，但 miRNA在正常乳腺茎和祖细胞中的作用尚未完全 调查。最近，据报道，miR146b参与了癌细胞迁移的抑制和 入侵和抑制乳腺癌转移。但是，miR146b在生理作用 正常的乳腺发育尚未确定。该应用的目的是 发现miR146b在乳腺祖细胞的生存和自我更新中的作用 确定其下游分子靶标。我们的中心假设是miR146b促进肺泡 通过激活Stat-5和抑制Stat-3，祖细胞的存活率和自我更新。 Stat-5在怀孕期间在肺泡细胞的存活和自我更新中起着至关重要的作用，而Stat-3发挥了A 在犯罪过程中，在乳腺死亡中的关键作用。我们将通过 以下特定目的：特定目的1：证明mir146b促进生存和自我更新 在乳腺肺泡祖细胞中，这将通过体外操纵的表达来实现 MiR146b在多能，导管和肺泡祖细胞中，衍生自乳腺上皮细胞系和 在源自雌性BALB/C处女和怀孕小鼠的肺泡祖细胞中。特定目标2：阐明 miR146b在抑制Stat-3和Stat-5激活中的作用。荧光素酶记者和CHIP分析将 用于确认这两个基因的miR146b调节。我们研究的长期目标是阐明 microRNA在乳腺茎和祖细胞存活和自我更新中的作用。