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：
8496767
负责人：
MICHELE A BATTLE
金额：
$ 30.13万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
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

来源：
https://reporter.nih.gov/project-details/8496767
关键词：
Anterior Automobile Driving Bile Acids Cells Characteristics DNA Data Defect Development Duodenum Economics Elements Engineering Enterocytes Epithelium Failure Fatty acid glycerol esters GATA4 transcription factor Gene Expression Genes Goals Health In Vitro Individual Intestines Knowledge Laboratories Lead Lipids Liquid substance Living Costs Maintenance Molecular Molecular Profiling Morbidity - disease rate Mus Nutrient Outcome Parenteral Nutrition Pathway interactions Patients Pharmacologic Substance Play Process Quality of life Repression Role Site Small Intestines Specificity Testing Time Tissues Transcription Coactivator Transcription Repressor/Corepressor Transplantation Zinc Fingers absorption bile acid transporter cholesterol absorption combat functional restoration ileum improved insight intestinal epithelium jejunum mortality mutant novel programs transcription factor

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

描述（由申请人提供）：控制建立和维护具有完成区域特定功能的肠上皮细胞的机制尚不清楚。我们实验室的长期目标是定义在肠道中创建这种功能特异性所需的调节器和途径，并最终操纵这些控制功能的途径。我们的初步研究表明，空肠中锌指转录因子GATA4的丧失损害了空肠身份，并且功能表明GATA4在赋予空肠身份中起主要作用。因此，推动该提议的中心假设是，沿小肠的前轴沿着前后轴的GATA4限制以赋予区域特异性对肠上皮。我们在目标1中提出，以确定沿小肠上皮前轴的GATA4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AIM 2中的研究将定义控制小肠上皮前轴GATA4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，该位点通常不存在GATA4（AIM 3）。拟议的研究的完成有望阐明单个转录因子调节肠道区域认同的机制。这很重要，因为这些研究将提供有关确定肠上皮功能命运的基本过程的知识