The role of SMAD1 and SATB2 in colon patterning

区域性规范描述了将特定特征和功能归因于胃肠道不同部分的过程。骨形态发生蛋白(BMP)信号是在模式生物和多能干细胞来源的人结肠器官(HCOs)中正确形成结肠模式所必需的。使用HCOS作为模型系统，我们建议研究BMP信号如何建立发育中的结肠的基因组图景。我们假设，在人类结肠模式形成过程中，骨形态发生蛋白(BMPs)诱导上皮SATB2和间质BCOR、GATA2和GATA3的表达，这是建立支持结肠mRNAs转录和抑制小肠mRNAs表达的基因组环境所必需的。我们的建议包括两个具体目标。目的1：确定骨形态发生蛋白(BMP)诱导人多能干细胞分化为结肠祖细胞的分子机制。目的2：确定SATB2是否介导了结肠上皮的构型。拟议研究的成功将为结肠分化提供独特的机制见解，并找到新的治疗靶点来治疗溃疡性结肠炎和结肠炎相关癌症，这些癌症已知具有图案缺陷。

Regional specification describes a process by which specific characteristics and function are ascribed to different parts of the gastrointestinal tract. Bone morphogenetic protein (BMP) signaling in necessary for proper patterning of the colon in model organisms and in pluripotent stem cell derived human colonic organoids (HCOs). Using HCOs as a model system, we propose to examine how BMP signaling establishes the genomic landscape of the developing colon. We hypothesize that during human colonic patterning, bone morphogenetic proteins (BMPs) induce the expression of epithelial SATB2 and mesenchymal BCOR, GATA2 and GATA3 that are required to establish a genomic environment that supports the transcription of colonic mRNAs and represses the expression of small intestinal mRNAs. Our proposal consists of 2 specific aims. Aim 1: Determine the molecular mechanisms through which BMP patterns colonic progenitors from human pluripotent stem cells. Aim 2: Determine if SATB2 mediates the patterning of the colonic epithelium. Success in the proposed studies will provide unique mechanistic insights into colonic differentiation as well as identify novel therapeutic targets to treat ulcerative colitis and colitis associated cancers which are known to display patterning defects.