Transcriptional Mechanisms of Tumor Suppression

肿瘤抑制的转录机制

基本信息

  • 批准号:
    9296102
  • 负责人:
  • 金额:
    $ 35.46万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-07-01 至 2020-06-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): After decades of outstanding research, the discovery of common genetic mutations occurring in colorectal cancer is nearing saturation. The next frontier will focus on identifying mechanisms downstream of these mutations that result in cancer progression. This proposal's main objective is to describe the transcriptional regulatory mechanisms by which the transcription factors CDX2 and SMAD4 suppress colon tumor progression. The central hypothesis is that these transcription factors stabilize tumors by maintaining chromatin structure and transcription factor regulatory networks that occur in normal, differentiated tissue. The rationale supporting this hypothesis is that 1) CDX2 and SMAD4 each function in development to establish the normal colon epithelium; and 2) that CDX2 and SMAD4 are each silenced or mutated during colon tumor progression. Aim 1 of the proposed work will take advantage of new mouse models to inactivate CDX2 in early and late cancer conditions to identify whether CDX2's transcriptional regulatory targets or control of chromatin structure are compromised in a way to support cancer growth. Preliminary evidence demonstrates CDX2-inactivation does indeed exacerbate the phenotype of a common oncogenic mouse model and that enhancer chromatin is altered when CDX2 is inactivated. Aim 2 will focus on elucidating the function of SMAD4 in colonic polyps. SMAD4 is one of the most frequently mutated genes in colon cancer but its transcriptional regulatory mechanisms in adenomas are unclear. A novel mouse model will be employed to inactivate SMAD4 in colonic polyps and immediately determine the consequences of SMAD4 loss on gene regulation and tumor chromatin structure. Finally, despite having similar functions in promoting tumor suppression and tissue differentiation, cooperativity between CDX2 and SMAD4 has not been investigated. Aim 3 will use a new mutant mouse to test for a genetic interaction between CDX2 and SMAD4 in the colon and potentially reveal a novel mechanism of tumor suppression. Existing research systems are unable to study the direct consequence of CDX2 or SMAD4 loss on tumor chromatin regulation in vivo. This approach is innovative in that we have assembled multiple animal models of colorectal cancer in which transcription factor knockout can be induced with precise temporal resolution. This system thus enables detailed genome-scale experiments to interrogate tumor transcriptional regulation. The proposed research is significant in that it is expected to identify a direct connection between tumor suppressing transcription factors, regulation of tumor chromatin structure, and novel mechanisms of transcriptional regulation of tumor progression.
 描述(由申请人提供):经过数十年的杰出研究,发现结直肠癌中常见的基因突变已接近饱和。下一个前沿将集中在确定导致癌症进展的这些突变的下游机制。该提案的主要目的是描述转录因子CDX 2和SMAD 4抑制结肠肿瘤进展的转录调控机制。核心假设是这些转录因子通过维持正常分化组织中出现的染色质结构和转录因子调控网络来稳定肿瘤。支持这一假设的基本原理是1)CDX 2和SMAD 4各自在发育中起作用以建立正常的结肠上皮;和2)CDX 2和SMAD 4各自在结肠肿瘤进展期间沉默或突变。拟议工作的目的1将利用新的小鼠模型在早期和晚期癌症条件下抑制CDX 2,以确定CDX 2的转录调控靶点或染色质结构的控制是否以支持癌症生长的方式受到损害。初步证据表明,CDX 2失活确实会加剧常见致癌小鼠模型的表型,并且当CDX 2失活时,增强子染色质发生改变。目的二是阐明SMAD 4在结肠息肉中的作用。SMAD 4是结肠癌中最常见的突变基因之一,但其在腺瘤中的转录调控机制尚不清楚。将采用一种新的小鼠模型来检测结肠息肉中的SMAD 4,并立即确定SMAD 4丢失对基因调控和肿瘤染色质结构的影响。最后,尽管在促进肿瘤抑制和组织分化方面具有相似的功能,但尚未研究CDX 2和SMAD 4之间的协同性。目标3将使用一种新的突变小鼠来测试结肠中CDX 2和SMAD 4之间的遗传相互作用,并可能揭示一种新的肿瘤抑制机制。 现有的研究系统无法在体内研究CDX 2或SMAD 4缺失对肿瘤染色质调控的直接后果。这种方法是创新的,因为我们已经组装了多种结肠直肠癌动物模型,其中转录因子敲除可以以精确的时间分辨率诱导。因此,该系统能够进行详细的基因组规模的实验来询问肿瘤转录调控。这项研究的意义在于,它有望确定肿瘤抑制转录因子、肿瘤染色质结构调控和肿瘤进展转录调控新机制之间的直接联系。

项目成果

期刊论文数量(0)
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专利数量(0)

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MICHAEL P. VERZI其他文献

MICHAEL P. VERZI的其他文献

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{{ truncateString('MICHAEL P. VERZI', 18)}}的其他基金

Mechanisms of Serrated Colon Tumor Suppression
锯齿状结肠肿瘤抑制机制
  • 批准号:
    10681608
  • 财政年份:
    2023
  • 资助金额:
    $ 35.46万
  • 项目类别:
Mechanisms Driving Metabolic Shifts in the Intestinal Epithelium
驱动肠上皮代谢变化的机制
  • 批准号:
    10773359
  • 财政年份:
    2021
  • 资助金额:
    $ 35.46万
  • 项目类别:
Mechanisms Driving Metabolic Shifts in the Intestinal Epithelium
驱动肠上皮代谢变化的机制
  • 批准号:
    10623339
  • 财政年份:
    2021
  • 资助金额:
    $ 35.46万
  • 项目类别:
Mechanisms Driving Metabolic Shifts in the Intestinal Epithelium
驱动肠上皮代谢变化的机制
  • 批准号:
    10390788
  • 财政年份:
    2021
  • 资助金额:
    $ 35.46万
  • 项目类别:
Transcriptional Mechanisms of Tumor Suppression
肿瘤抑制的转录机制
  • 批准号:
    9044741
  • 财政年份:
    2015
  • 资助金额:
    $ 35.46万
  • 项目类别:
Mechanisms underlying YY1 control of intestinal epithelial homeostasis
YY1控制肠上皮稳态的机制
  • 批准号:
    8565630
  • 财政年份:
    2013
  • 资助金额:
    $ 35.46万
  • 项目类别:
Mechanisms underlying YY1 control of intestinal epithelial homeostasis
YY1控制肠上皮稳态的机制
  • 批准号:
    8689012
  • 财政年份:
    2013
  • 资助金额:
    $ 35.46万
  • 项目类别:
Transcriptional Regulation of the Intestinal Epithelium
肠上皮的转录调控
  • 批准号:
    8384240
  • 财政年份:
    2010
  • 资助金额:
    $ 35.46万
  • 项目类别:
Transcriptional Regulation of the Intestinal Epithelium
肠上皮的转录调控
  • 批准号:
    8627233
  • 财政年份:
    2010
  • 资助金额:
    $ 35.46万
  • 项目类别:
Transcriptional Regulation of the Intestinal Epithelium
肠上皮的转录调控
  • 批准号:
    7952403
  • 财政年份:
    2010
  • 资助金额:
    $ 35.46万
  • 项目类别:

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