Solving regulatory circuits controlling gut organogenesis

解决控制肠道器官发生的调节回路

• 批准号: 9888387
• 负责人: Isabelle S Peter
• 金额: $ 41.13万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888387
• 关键词: Address; Animals; Anterior; Anus; Appearance; Automobile Driving; Basic Science; Behavior; Biological Assay; Body part; Cell model; Cells; Collection; Complex; Computer Models; Data; Data Analyses; Defect; Development; Developmental Biology; Developmental Gene; Developmental Process; Disease; Embryo; Endoderm; Endoderm Cell; Factor Analysis; Feedback; Fertilization; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic Transcription; Genomics; Goals; HNF4A gene; Hindgut; Hour; Image; In Situ Hybridization; Individual; Inferior esophageal sphincter structure; Instruction; Lead; Life; Logic; Malignant Neoplasms; Midgut; Molecular; Morphology; Oral cavity; Organ; Organism; Organogenesis; Orthologous Gene; Pattern; Physiological; Primitive foregut structure; Process; Pyloric sphincter structure; Recording of previous events; Regulation; Regulator Genes; Reporter; Repression; Reproducibility; Research; Research Proposals; Role; Sea Urchins; Side; Spatial Behavior; Specific qualifier value; Sphincter; Structure; System; Testing; Time; Tissue-Specific Gene Expression; Tube; Vertebrates; Work; base; cell fate specification; cell type; design; experimental analysis; experimental study; gastrointestinal system; genome-wide analysis; insight; interest; knock-down; nano-string; network models; transcription factor

Solving regulatory circuits controlling gut organogenesis An important question in developmental biology is how the spatial organization of body parts, organs, and cell types within the animal body plan is acquired with such accuracy and reproducibility during animal development according to genomic instructions. Gene regulatory networks (GRNs) encode these instructions and thereby provide the mechanisms for spatial organization of the body plan. GRNs control the expression of transcriptional regulators that in turn regulate the expression of cell-fate specific genes. Due to the challenges associated with experimentally analyzing GRNs in developing animals, there are so far only few developmental processes understood at the GRN level. In this project we are beginning to analyze the GRN underlying organogenesis of the gut, a developmental process that is broadly shared among animals. In order to access the developmental mechanisms underlying gut development, we will use a relatively simple deuterostome animal, the sea urchin, which facilitates system level analyses even of complicated processes such as organogenesis that might not be easily addressed in vertebrates. The sea urchin larval gut forms within 72h of fertilization and consists of multiple morphologically distinct compartments including foregut, midgut, hindgut, sphincters, mouth and anus. We recently acquired spatial expression data for over 270 regulatory genes encoding transcription factors, showing that the different compartments of the gut are distinguished at the molecular level by expression of unique combinations of transcription factors. These compartment-specific transcription factor modules are expressed prior to the appearance of morphological structure and are usually expressed over long periods of time throughout development. We will complete this analysis to identify transcription factor combinations expressed in individual endodermal cell fates within these compartments. The goal of this project is to identify the mechanisms leading to the distinct specification of foregut, midgut, hindgut, and sphincters during gut development. We will thus test the function of compartment-specific transcription factor modules by perturbation of each transcription factor and by analyzing its role in the regulation of other transcription factors and in the formation of the respective compartments. As insights on regulatory interactions accumulate, we will generate GRN models to visualize the topology of regulatory circuits and to test their dynamic and spatial behavior. The result of this project will reveal the regulatory mechanisms that control the distinct specification of the major compartments of the sea urchin gut, mechanisms that might in some form also contribute to the patterning of the anterior/posterior axis of the gut in other animals.

解决控制肠道器官发生的调节回路 发育生物学的一个重要问题是身体部位、器官和细胞的空间组织如何 动物体内计划中的类型是在动物发育过程中以如此精确和可重复性获得的 根据基因组说明。基因调控网络（GRN）对这些指令进行编码，从而 提供身体规划的空间组织机制。 GRNs 控制转录因子的表达 反过来调节细胞命运特定基因的表达的调节因子。由于相关的挑战 通过实验分析发育中动物的 GRN，迄今为止只有很少的发育过程 在GRN级别上理解。在这个项目中，我们开始分析 GRN 的器官发生 肠道是动物广泛共有的一个发育过程。为了获得发展 肠道发育的机制，我们将使用一种相对简单的后口动物，海胆， 这有助于系统级分析，甚至是复杂的过程，例如器官发生，这可能不是 在脊椎动物中很容易解决。海胆幼虫肠道在受精后 72 小时内形成，由多个 形态上不同的区室，包括前肠、中肠、后肠、括约肌、口腔和肛门。我们 最近获得了超过 270 个编码转录因子的调控基因的空间表达数据，显示 肠道的不同区室在分子水平上通过独特的表达来区分 转录因子的组合。这些区室特异性转录因子模块被表达 在形态结构出现之前并且通常在很长一段时间内表达 整个开发过程中。我们将完成此分析，以确定表达的转录因子组合 这些区室中单个内胚层细胞的命运。该项目的目标是确定 导致肠道中前肠、中肠、后肠和括约肌不同规格的机制 发展。因此，我们将通过扰动测试区室特异性转录因子模块的功能 每个转录因子并通过分析其在其他转录因子的调节中的作用以及 各个隔室的形成。随着对监管相互作用的见解不断积累，我们将产生 GRN 模型可可视化调节电路的拓扑并测试其动态和空间行为。这 该项目的结果将揭示控制主要专业不同规范的监管机制 海胆肠道的区室，可能以某种形式也有助于形成海胆肠道的模式的机制 其他动物肠道的前/后轴。