Determining the Mechanisms Regulating Functional Regionalization of the Intestine

确定肠道功能分区的调节机制

基本信息

  • 批准号:
    8080267
  • 负责人:
  • 金额:
    $ 31.22万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-07-01 至 2015-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The mechanisms controlling establishment and maintenance of enterocytes with the capacity to accomplish regionally specific functions are unclear. The long-term goal of our laboratory is to define the regulators and pathways required to create this functional specificity in the intestine and ultimately to manipulate these pathways to control function. Our preliminary studies have shown that loss of the zinc finger transcription factor GATA4 in the jejunum compromises jejunal identity and function suggesting that GATA4 plays a dominant role in conferring jejunal identity. Therefore, the central hypothesis driving this proposal is that restriction of GATA4 along the anterior-posterior axis of the small intestine is required to confer regional specificity to the intestinal epithelium. We propose in Aim 1 to identify the timing of GATA4 restriction along the anterior-posterior axis of the small intestinal epithelium and the extent to which such restriction corresponds with the activation of the jejunal-specific gene expression program. Our studies in Aim 2 will define the mechanisms controlling the restriction of GATA4 along the anterior-posterior axis of the small intestinal epithelium. To determine if GATA4 is sufficient to confer jejunal fate in the intestine, we will ectopically express GATA4 in the ileum, a site where GATA4 is normally absent (Aim 3). Completion of the proposed studies is expected to elucidate the mechanism through which an individual transcription factor acts to regulate regional identity in the intestine. This is significant because these studies will provide knowledge into the basic processes governing the determination of the functional fate of the intestinal epithelium, a prerequisite to the development of novel therapies to combat intestinal failure PUBLIC HEALTH RELEVANCE: The goal of the current proposal is to determine how restricted expression of the transcription factor GATA4 in the small intestine controls the establishment and maintenance of functional regionalization in the intestine. Completion of the proposed studies will provide knowledge into the basic processes that govern delineation of the duodenum, jejunum, and ileum, a process that is not yet understood. Such insight has the potential to lead to the development of novel therapies to combat intestinal failure such as the ability to use pharmaceuticals to restore lost functions to intestinal tissue and to engineer intestinal tissue in vitro for transplantation.
描述(由申请人提供):控制具有完成区域特定功能的能力的肠细胞的建立和维持的机制尚不清楚。我们实验室的长期目标是确定在肠道中产生这种功能特异性所需的调节因子和途径,并最终操纵这些途径来控制功能。我们的初步研究表明,空肠中锌指转录因子 GATA4 的缺失会损害空肠特性和功能,表明 GATA4 在赋予空肠特性中起主导作用。因此,推动这一提议的中心假设是,需要沿着小肠的前后轴限制 GATA4,以赋予肠上皮区域特异性。我们在目标 1 中建议确定 GATA4 沿小肠上皮前后轴限制的时间,以及这种限制与空肠特异性基因表达程序的激活相对应的程度。我们在目标 2 中的研究将定义控制 GATA4 沿着小肠上皮的前后轴的限制的机制。为了确定 GATA4 是否足以在肠道中赋予空肠命运,我们将在回肠中异位表达 GATA4,这是 GATA4 通常不存在的部位(目标 3)。拟议研究的完成预计将阐明单个转录因子调节肠道区域特征的机制。这很重要,因为这些研究将为决定肠上皮功能命运的基本过程提供知识,这是开发对抗肠道衰竭的新疗法的先决条件 公共健康相关性:当前提案的目标是确定小肠中转录因子 GATA4 的限制性表达如何控制肠道功能区域化的建立和维持。完成拟议的研究将为控制十二指肠、空肠和回肠的基本过程提供知识,这一过程尚不清楚。这种见解有可能导致开发对抗肠道衰竭的新疗法,例如使用药物恢复肠道组织失去的功能以及在体外改造肠道组织以进行移植的能力。

项目成果

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MICHELE A BATTLE其他文献

MICHELE A BATTLE的其他文献

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{{ truncateString('MICHELE A BATTLE', 18)}}的其他基金

Defining GATA4’s Molecular Function in Gastric Cell Biology
定义 GATA4 在胃细胞生物学中的分子功能
  • 批准号:
    10536433
  • 财政年份:
    2022
  • 资助金额:
    $ 31.22万
  • 项目类别:
Defining GATA4’s Molecular Function in Gastric Cell Biology
定义 GATA4 在胃细胞生物学中的分子功能
  • 批准号:
    10675020
  • 财政年份:
    2022
  • 资助金额:
    $ 31.22万
  • 项目类别:
Determining the Mechanisms Regulating Functional Regionalization of the Intestine
确定肠道功能分区的调节机制
  • 批准号:
    7992215
  • 财政年份:
    2010
  • 资助金额:
    $ 31.22万
  • 项目类别:
Determining the Mechanisms Regulating Functional Regionalization of the Intestine
确定肠道功能分区的调节机制
  • 批准号:
    8296316
  • 财政年份:
    2010
  • 资助金额:
    $ 31.22万
  • 项目类别:
Determining the Mechanisms Regulating Functional Regionalization of the Intestine
确定肠道功能分区的调节机制
  • 批准号:
    8496767
  • 财政年份:
    2010
  • 资助金额:
    $ 31.22万
  • 项目类别:
Determining the Mechanisms Regulating Functional Regionalization of the Intestine
确定肠道功能分区的调节机制
  • 批准号:
    8683158
  • 财政年份:
    2010
  • 资助金额:
    $ 31.22万
  • 项目类别:
The role of HNF4 in gastrointestinal development
HNF4在胃肠道发育中的作用
  • 批准号:
    6793478
  • 财政年份:
    2004
  • 资助金额:
    $ 31.22万
  • 项目类别:
The role of HNF4 in gastrointestinal development
HNF4在胃肠道发育中的作用
  • 批准号:
    6914445
  • 财政年份:
    2004
  • 资助金额:
    $ 31.22万
  • 项目类别:
The role of HNF4 in gastrointestinal development
HNF4在胃肠道发育中的作用
  • 批准号:
    7093044
  • 财政年份:
    2004
  • 资助金额:
    $ 31.22万
  • 项目类别:

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  • 批准号:
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