Determining the Mechanisms Regulating Functional Regionalization of the Intestine

描述（由申请方提供）：控制肠上皮细胞建立和维持的机制尚不清楚，肠上皮细胞具有完成区域特异性功能的能力。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剂和途径，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GATA 4在空肠中的损失会损害空肠的身份和功能，这表明GATA 4在赋予空肠身份中起主导作用。因此，驱动该提议的中心假设是，需要沿着小肠的前-后轴沿着限制GATA 4以赋予肠上皮区域特异性。我们在目的1中提出，确定GATA 4限制沿着小肠上皮前后轴的时间，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。我们在目的2中的研究将确定控制GATA 4沿小肠上皮的前-后轴沿着限制的机制。为了确定GATA 4是否足以在肠中赋予空肠命运，我们将在回肠中异位表达GATA 4，回肠是GATA 4通常不存在的部位（目的3）。完成拟议的研究有望阐明单个转录因子调节肠道区域身份的机制。这是重要的，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，这是开发对抗肠衰竭的新疗法的先决条件 公共卫生相关性：目前的建议的目标是确定如何限制表达的转录因子GATA 4在小肠控制建立和维持功能区域化的肠道。完成拟议的研究将提供有关十二指肠、空肠和回肠描绘的基本过程的知识，这是一个尚未理解的过程。这种见解有可能导致开发新的治疗方法来对抗肠衰竭，例如使用药物恢复肠组织失去的功能和体外工程肠组织用于移植的能力。

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.