The role of SMAD1 and SATB2 in colon patterning

SMAD1 和 SATB2 在结肠模式中的作用

• 批准号: 10334570
• 负责人: Jorge O Munera
• 金额: $ 14.6万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-05 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10334570
• 关键词: Animal Model; Biological Models; Bone Morphogenetic Proteins; Centers of Research Excellence; Characteristics; Colon; Defect; Digestive System Disorders; Environment; Epithelial; GATA3 gene; Gastrointestinal tract structure; Genetic Transcription; Genomics; Human; Liver diseases; Mediating; Mesenchymal; Messenger RNA; Molecular; Organoids; Pattern; Pluripotent Stem Cells; Process; Role; Signaling Protein; Small Intestines; Ulcerative Colitis; colitis associated cancer; human pluripotent stem cell; insight; new therapeutic target; progenitor; success

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.

区域特异性描述了胃肠道不同部分的特定特征和功能的过程。骨形态发生蛋白（BMP）信号传导对于模型生物体和多能干细胞衍生的人结肠类器官（HCO）中结肠的适当模式化是必要的。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结肠的基因组景观。我们假设，在人类结肠模式，骨形态发生蛋白（BMP）诱导上皮SATB 2和间充质BCOR，GATA 2和GATA 3的表达，需要建立一个基因组环境，支持结肠mRNA的转录和抑制小肠mRNA的表达。我们的建议包括两个具体目标。目的1：确定BMP从人多能干细胞分化为结肠祖细胞的分子机制。目的2：确定SATB 2是否介导结肠上皮的图案化。拟议研究的成功将为结肠分化提供独特的机制见解，并确定治疗溃疡性结肠炎和结肠炎相关癌症的新治疗靶点，这些癌症已知显示图案缺陷。