Functional Evaluation of microRNAs in Pancreatic Neoplasia

microRNA 在胰腺肿瘤中的功能评估

基本信息

  • 批准号:
    8464662
  • 负责人:
  • 金额:
    $ 25.71万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-04-01 至 2015-03-31
  • 项目状态:
    已结题

项目摘要

MicroRNAs (miRNAs) are 18-24 nucleotide RNA molecules that regulate the stability or translational efficiency of complementary target mRNAs. miRNAs participate in a diverse array of cellular processes including proliferation, apoptosis, and differentiation. Moreover, globally abnormal miRNA expression patterns appear to be a ubiquitous feature of human cancer cells. Work from our laboratory and others has established that miRNAs function as critical downstream components of several important oncogenic and tumor suppressor pathways. Furthermore, some miRNAs themselves act as novel oncogenes and tumor suppressors. These findings suggest a causative role for miRNA dysregulation in cancer pathogenesis. We have recently classified miRNA expression patterns in pancreatic cancer cells and identified a cohort of miRNAs that are frequently abnormally expressed compared to normal cells. Based on these findings, we now propose a series of experiments designed to test the following central hypothesis: Key miRNAs that are controlled by critical signaling pathways and are abnormally expressed in pancreatic cancer cells act as novel oncogenes and tumor suppressors. We will test these hypotheses by pursuing three specific aims. In Aim 1, we will functionally evaluate the consequences of miRNA dysregulation in vitro by examining neoplastic cellular phenotypes following enforced expression or inhibition of selected miRNAs. We will also employ somatic cell gene knockout methodologies to examine the consequences of complete loss-of-function of specific miRNAs. Finally, we will initiate mechanistic studies of the role of miRNAs in pancreatic cancer by characterizing an important miRNA:target mRNA interaction. In Aim 2, we will take advantage a novel zebrafish model of pancreatic cancer developed by our co- investigator Dr. Leach. By expressing miRNAs in this model specifically in the developing pancreas, we will be able to assess the contribution of miRNAs to pancreatic cancer pathogenesis in vivo in a high-throughput manner. Finally, in Aim 3, we will characterize a novel mouse model that we have generated with loss of function of a miRNA with anti-tumorigenic activity that we have shown to be frequently absent in pancreatic cancer cells. We will also breed these mice to a well-established model of pancreatic cancer to specifically assess the contribution of loss of this miRNA to disease progression. We envision that these studies will contribute significantly to our understanding of the molecular basis of pancreatic cancer and may reveal novel pathways that are amenable to therapeutic intervention. RELEVANCE (See instructions): Pancreatic ductal adenocarcinoma (pancreatic cancer) is the fourth most common cause of cancer-related death, accounting for approximately 33,000 lives each year in the United States. The five year survival rate of <5% underscores the ineffectiveness of current therapies and the profound direness of this disease. We propose to study the role of a recently-described class of molecules called microRNAs in pancreatic cancer biology, with the hope of revealing new insights that could lead to novel therapeutic strategies.
microRNA(miRNAs)是一种18-24个核苷酸的RNA分子,其调节细胞的稳定性或翻译。 互补靶mRNA的效率。miRNAs参与多种细胞过程 包括增殖、凋亡和分化。此外,总体上异常的miRNA表达 模式似乎是人类癌细胞的普遍特征。我们实验室和其他人的工作 建立了miRNAs作为几种重要的致癌基因的关键下游成分的功能, 肿瘤抑制通路。此外,一些miRNAs本身作为新的癌基因和肿瘤 抑制剂这些发现表明miRNA失调在癌症发病机制中的致病作用。 最近,我们对胰腺癌细胞中的miRNA表达模式进行了分类,并确定了一种新的表达模式。 与正常细胞相比经常异常表达的一组miRNA。基于这些 根据这些发现,我们现在提出一系列实验,旨在检验以下中心假设: 由关键信号通路控制的miRNAs在细胞中异常表达, 胰腺癌细胞作为新的癌基因和肿瘤抑制因子。我们将检验这些假设 实现三个具体目标。在目标1中,我们将从功能上评估miRNA的结果, 通过检查在强制表达或抑制后的肿瘤细胞表型来体外失调 选择miRNAs。我们还将采用体细胞基因敲除方法来检查 特定miRNA功能完全丧失的后果。最后,我们将开始进行以下机制研究: miRNA在胰腺癌中的作用,通过表征一个重要的miRNA:靶mRNA相互作用。在 目的2,我们将利用我们的合作开发的一种新的斑马鱼胰腺癌模型, 调查员利奇博士通过在这个模型中表达miRNAs,特别是在发育中的胰腺中, 能够在体内以高通量的方式评估miRNA对胰腺癌发病机制的贡献, 方式最后,在目标3中,我们将描述一个新的小鼠模型,我们已经产生了损失的 具有抗肿瘤活性的miRNA的功能,我们已经证明在胰腺癌中经常缺乏, 癌细胞我们还将这些小鼠培育成一个良好的胰腺癌模型, 评估该miRNA的缺失对疾病进展的贡献。我们预计这些研究将 有助于我们了解胰腺癌的分子基础,并可能揭示 新的途径,适合治疗干预。 相关性(参见说明): 胰腺导管腺癌(胰腺癌)是第四个最常见的癌症相关的原因, 死亡,在美国每年约有33,000人死亡。五年生存率 <5%强调了目前治疗的无效性和这种疾病的严重性。我们 我建议研究最近描述的一类称为microRNA的分子在胰腺癌中的作用 生物学,希望揭示新的见解,可能导致新的治疗策略。

项目成果

期刊论文数量(0)
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Joshua T Mendell其他文献

Tumors line up for a letdown
肿瘤排队等待失望。
  • DOI:
    10.1038/ng0709-768
  • 发表时间:
    2009-07-01
  • 期刊:
  • 影响因子:
    29.000
  • 作者:
    Joshua T Mendell
  • 通讯作者:
    Joshua T Mendell

Joshua T Mendell的其他文献

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{{ truncateString('Joshua T Mendell', 18)}}的其他基金

The role of long noncoding RNA CRNDE in normal physiology and cancer
长链非编码RNA CRNDE在正常生理和癌症中的作用
  • 批准号:
    10715065
  • 财政年份:
    2023
  • 资助金额:
    $ 25.71万
  • 项目类别:
The intersection of RNA biology and tumor biology
RNA生物学与肿瘤生物学的交叉点
  • 批准号:
    8953055
  • 财政年份:
    2015
  • 资助金额:
    $ 25.71万
  • 项目类别:
The intersection of RNA biology and tumor biology
RNA生物学与肿瘤生物学的交叉点
  • 批准号:
    10213661
  • 财政年份:
    2015
  • 资助金额:
    $ 25.71万
  • 项目类别:
The intersection of RNA biology and tumor biology
RNA生物学与肿瘤生物学的交叉点
  • 批准号:
    9125799
  • 财政年份:
    2015
  • 资助金额:
    $ 25.71万
  • 项目类别:
c-Myc-regulated microRNAs in normal and pathologic cellular physiology
正常和病理细胞生理学中 c-Myc 调节的 microRNA
  • 批准号:
    7915972
  • 财政年份:
    2009
  • 资助金额:
    $ 25.71万
  • 项目类别:
Functional Evaluation of microRNAs in Pancreatic Neoplasia
microRNA 在胰腺肿瘤中的功能评估
  • 批准号:
    7651550
  • 财政年份:
    2009
  • 资助金额:
    $ 25.71万
  • 项目类别:
c-Myc-regulated microRNAs in normal and pathologic cellular physiology
正常和病理细胞生理学中 c-Myc 调节的 microRNA
  • 批准号:
    8026614
  • 财政年份:
    2007
  • 资助金额:
    $ 25.71万
  • 项目类别:
c-Myc-regulated microRNAs in normal and pathologic cellular physiology
正常和病理细胞生理学中 c-Myc 调节的 microRNA
  • 批准号:
    8712397
  • 财政年份:
    2007
  • 资助金额:
    $ 25.71万
  • 项目类别:
c-Myc-regulated microRNAs in normal and pathologic cellular physiology
正常和病理细胞生理学中 c-Myc 调节的 microRNA
  • 批准号:
    8578048
  • 财政年份:
    2007
  • 资助金额:
    $ 25.71万
  • 项目类别:
c-Myc-regulated microRNAs in normal and pathologic cellular physiology
正常和病理细胞生理学中 c-Myc 调节的 microRNA
  • 批准号:
    7766253
  • 财政年份:
    2007
  • 资助金额:
    $ 25.71万
  • 项目类别:

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