Determining the Mechanisms Regulating Functional Regionalization of the Intestine

描述(由申请人提供)：控制建立和维持具有完成区域特定功能的能力的肠细胞的机制尚不清楚。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，锌指转录因子GATA4在空肠中的缺失损害了空肠的特性和功能，这表明GATA4在赋予空肠特性方面起着主导作用。因此，支持这一建议的中心假设是，GATA4沿小肠前后轴的限制需要赋予肠上皮区域特异性。在目标1中，我们建议确定GATA4沿小肠上皮前后轴的限制时间，以及这种限制与空肠特异基因表达程序激活的程度相对应。我们在目标2中的研究将确定GATA4沿小肠上皮前-后轴的限制机制。为了确定GATA4是否足以赋予空肠在肠道中的命运，我们将在回肠异位表达GATA4，这是一个通常缺乏GATA4的位置(目标3)。这项拟议研究的完成有望阐明单个转录因子调节肠道区域特性的机制。这一点意义重大，因为这些研究将提供关于决定肠上皮功能命运的基本过程的知识，这是开发抗击肠道衰竭的新疗法的先决条件。

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