Cell-Cell Interactions during intestinal development

肠道发育过程中细胞与细胞的相互作用

• 批准号: 8314055
• 负责人: DEBORAH L. GUMUCIO
• 金额: $ 31.36万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314055
• 关键词: Agglutination; Area; Beryllium; Biomedical Engineering; Blood Vessels; Cell Communication; Cells; Competence; Coupling; DNA; Data; Defect; Development; Diffusion; Elements; Embryo; Enhancers; Ensure; Epithelial; Epithelium; Erinaceidae; Event; Feathers; Fingers; Gene Targeting; Generations; Genes; Genetic; Genomics; Goals; Growth; Hair follicle structure; Hour; Human; Intestines; Investigation; Length; Life; Ligands; Link; Mediating; Mesenchymal; Mesenchyme; Modeling; Molecular; Morphogenesis; Mus; Nutrient; Operative Surgical Procedures; Organ; Pathology; Pattern; Process; Reaction; Signal Pathway; Signal Transduction; Skin; Small Intestines; Software Tools; Surface; System; Time; Tissues; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascular System; Villus; Work; absorption; appendage; design; in utero; insight; intestinal epithelium; intestinal villi; mouse model; notch protein; novel; prevent; public health relevance; smoothened signaling pathway

DESCRIPTION (provided by applicant): The impressively large absorptive surface area of the intestine is largely contributed by its length as well as the extensive surface amplification provided by millions of fingerlike villus projections. Congenital or acquired pathologies that result in significant loss of this intestinal surface area seriously compromise the ability of the intestine to absorb nutrients and can be life threatening. Work in the past project period has begun to identify some of the cellular and molecular mechanisms that control the formation of villi in utero in the murine model. The period between embryonic day (E) 14.5 and E15.5 (in the mouse) is particularly important since during this time, controlled morphogenic remodeling in both the epithelium and the underlying mesenchyme results in the emergence of villi. The Working Hypothesis underlying these studies is that: Villus development is actively inhibited by Bmp signaling prior to E14.5. At E14.5, epithelial Hh signals initiate villus development by promoting the formation of mesenchymal clusters. Cluster patterning proceeds via a Turing system and vascular coupling to these clusters precedes and is required for villus emergence. Importantly, since the morphological hallmarks of all of these events are also present in the human intestine, it is likely that the majority of the signaling paradigms uncovered in the mouse model will be applicable to the human intestine. This proposal makes use of genetic mouse models as well as a novel intestinal explant culture system to mechanistically dissect the interconnected signaling and patterning events involved in these surface- generating processes. Additionally, a new software tool that can recognize Hh-responsive signaling enhancers in genomic DNA with high efficiency will aid in the recognition of Hh target genes. The Specific Aims are designed to 1) Determine how Bmp signaling controls competence to form villi and establish which tissue (epithelium or mesenchyme) exerts this control; 2) Identify Hh target genes during the formation of mesenchymal clusters; and 3) Determine the relationship between vascular elements, forming clusters and cluster pattern. Through detailed analysis of these linked processes, the goal of these studies is to gain new insight into the formation of the intestinal absorptive surface. The ability to bioengineer organs from their cellular components will require not only that we elucidate the molecular signals that are important for morphogenesis and cell fate determination, but also that we understand the rules that govern the patterning of the functional units that comprise the organ. The unique focus of this investigation on signaling crosstalk in the nascent villus unit (epithelium, mesenchyme, vasculature) will have a major impact on our understanding of how intestinal villi are first formed in the embryo. PUBLIC HEALTH RELEVANCE: The surface of the small intestine is highly convoluted by finger-like projections called villi; this extended surface area is critical for efficient nutrient absorption. Loss of intestinal surface area either by congenital intestinal defects or by pathological or surgical events, can be life threatening. The ability to bioengineer the intestine from its cellular components will require not only that we elucidate the molecular signals that are important for morphogenesis and cell fate determination, but also that we understand the rules that govern the patterning of the functional units that comprise the organ. Currently, little is known about how villi are generated in utero. Through the study of mouse models with perturbed villus formation and through the analysis of a novel intestinal explant culture system, we propose to dissect the molecular processes responsible for villus emergence. The unique focus of this investigation on signaling crosstalk in the nascent villus unit (epithelium, mesenchyme, vasculature) will have a major impact on our understanding of how intestinal villi are first formed in the embryo.

描述（由申请人提供）：肠道的吸收表面积令人印象深刻，这在很大程度上是由于其长度以及数百万个指状绒毛突起提供的广泛表面放大。先天性或后天性病变导致肠道表面积的显著损失，严重损害肠道吸收营养物质的能力，并可能危及生命。在过去的项目期间的工作已经开始确定一些细胞和分子机制，控制绒毛在子宫内的小鼠模型。胚胎第14.5天和E15.5天（小鼠）之间的时期特别重要，因为在此期间，上皮和下层间充质的受控形态发生重塑导致绒毛出现。这些研究的工作假设是：绒毛发育在E14.5之前被Bmp信号积极抑制。在E14.5，上皮Hh信号通过促进间充质簇的形成启动绒毛发育。簇图案化通过图灵系统进行，并且与这些簇的血管耦合在绒毛出现之前并且是绒毛出现所需的。重要的是，由于所有这些事件的形态学特征也存在于人类肠道中，因此小鼠模型中发现的大多数信号传导模式可能适用于人类肠道。该提议利用遗传小鼠模型以及新型肠外植体培养系统来机械地剖析这些表面生成过程中涉及的相互关联的信号传导和图案化事件。此外，一种新的软件工具，可以识别Hh响应信号增强基因组DNA中的高效率将有助于识别Hh靶基因。具体目的旨在：1）确定Bmp信号传导如何控制绒毛形成能力，并确定哪种组织（上皮或间充质）发挥这种控制作用; 2）在间充质簇形成过程中鉴定Hh靶基因; 3）确定血管成分、簇形成和簇模式之间的关系。通过对这些相关过程的详细分析，这些研究的目标是获得对肠吸收表面形成的新见解。从细胞成分中生物工程器官的能力不仅需要我们阐明对形态发生和细胞命运决定重要的分子信号，而且还需要我们理解控制组成器官的功能单位模式的规则。这项研究的独特重点是新生绒毛单位（上皮，间充质，血管）中的信号串扰将对我们理解肠绒毛如何在胚胎中首次形成产生重大影响。 公共卫生关系：小肠的表面被称为绒毛的指状突起高度卷曲;这种扩展的表面积对于有效的营养吸收至关重要。先天性肠缺陷或病理或手术事件导致的肠表面积损失可能危及生命。从其细胞成分生物工程肠的能力将不仅需要我们阐明的分子信号，是重要的形态和细胞命运的决定，但我们也了解的规则，管理模式的功能单位，包括器官。目前，对绒毛在子宫内是如何产生的知之甚少。通过对绒毛形成受到干扰的小鼠模型的研究，并通过对一种新的肠外植体培养系统的分析，我们提出了解剖绒毛出现的分子过程。这项研究的独特重点是新生绒毛单位（上皮，间充质，血管）中的信号串扰将对我们理解肠绒毛如何在胚胎中首次形成产生重大影响。