Studies on intestine-enriched transcription factor, IKFL

转录因子的作用的研究提供了深入了解的调控机制，导致细胞特异性基因转录，并因此，控制不同的细胞谱系在发育过程中的分化。肠上皮由于其增殖能力，代表了一个连续的发育系统，因此为研究生物学重要过程提供了一个有吸引力的模型。 它还为鉴定和分析控制细胞生长和分化的因素提供了独特的机会。 因此，要深入了解肠上皮细胞中的转录调控机制，就需要鉴定和表征表现出有限表达模式的新型转录因子。 我们最近鉴定了肠富集的Kruppel样因子（IKLF; KLF 5），其为转录因子的Kruppel样家族（KLF）的新成员。 IKLF是一种锌指转录因子，其在肠隐窝上皮细胞中高度表达，表明IKLF在隐窝细胞的增殖和分化中起作用。 在本申请中，我们建议研究IKLF在发育过程中和成人组织中的细胞类型特异性表达，以开发具有IKLF基因靶向破坏的小鼠模型，并研究由于缺乏IKLF表达而导致的表型后果，作为确定其生物学功能的手段。我们的研究旨在更全面地描述IKLF表达的转录调控，并鉴定其下游靶基因。 拟议的分子和功能研究提供了一个机会，以了解IKLF介导的精氨酸特异性基因表达的生物学作用，作为一种手段，以进一步确定新的途径重要的肠组织的发展和分化。

Studies of the role of transcription factors have provided insights into the regulatory mechanisms that lead to cell-specific gene transcription and, as a result, control the differentiation of distinct cell lineages during development. The intestinal epithelium, because of its proliferative capacity, represents a continuous developmental system and therefore provides an attractive model to study biologically important processes. It also provides a unique opportunity for the identification and analysis of factors that control cell growth and differentiation. An in-depth understanding of the mechanisms which govern transcriptional regulation in intestinal epithelium therefore requires the identification and characterization of novel transcription factors which show a restricted pattern of expression. We have recently identified Intestinal-enriched Kruppel-Like Factor (IKLF;KLF5), a novel member of the Kruppel- like family (KLF) of transcription factors. IKLF is a zinc finger transcription factor which is highly expressed in epithelial cells of the intestinal crypts suggesting a role for IKLF in the proliferation and differentiation of crypt cells. In this application we propose to study the cell type specific expression of IKLF during development and in adult tissue, to develop a mouse model with targeted disruption of the IKLF gene and study the phenotypic consequences due to the lack of IKLF expression as a means of determining its biological function. Our studies are further designed to more fully describe the transcriptional regulation of IKLF expression, and identification of its downstream target gene(s). The proposed molecular and functional studies provide an opportunity to understand the biological role of IKLF in mediating intestine-specific gene expression as a means to further define the novel pathways important for the development and differentiation of intestinal tissue.