Administrative Supplement - Developmentally Programmed Remodeling of Apical ECM

行政补充 - 心尖 ECM 的发育编程重塑

• 批准号: 10740970
• 负责人: Maxwell Heiman
• 金额: $ 1.73万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10740970
• 关键词: Administrative Supplement; Adolescent; Adult; Afferent Neurons; Animals; Apical; Caenorhabditis elegans; Cells; Complex; Data; Development; Disease; Environment; Event; Extracellular Matrix; Gene Expression; Gene Expression Profiling; Genes; Hermaphroditism; Lead; Modeling; Morphogenesis; Neuroglia; Neurons; Neurotransmitters; Organ; Organism; Play; Process; Proteins; Role; Shapes; Structure; Surface; Testing; Therapeutic; Tissue Engineering; Tissues; Visualization; cell type; density; in vivo; innovation; male; mutant; nanoscale; novel; organ growth; sex; targeted delivery; therapeutic target

Abstract Apical extracellular matrix (aECM) coats the outward-facing surface of every organ, forming a barrier between the organism and its environment. Although it has been viewed historically as a static layer, aECM has been recently revealed to be dynamic across development and highly varied between cell types. It plays important roles in shaping organ morphogenesis and modulating cell activity. Identifying the regulatory mechanisms that control aECM composition and structure is therefore critical to understanding its role in development. Further, because aECM is highly accessible, there is enormous potential to manipulate it for targeted delivery of therapeutics or in tissue engineering. The major obstacles to studying aECM remodeling are that changes in aECM are difficult to visualize and need to be studied in vivo during highly dynamic processes that involve complex cell rearrangements. This project overcomes these obstacles by using an innovative model of developmentally programmed aECM remodeling. Preliminary data lead to the hypothesis that aECM structure is a discrete modular feature of cell identity, analogous to neurotransmitter types in neurons, rather than a continuum of stiffness/density. The C. elegans cuticle is an aECM that forms barrier between the animal and its environment. In order to directly access the external environment, the ciliated endings of some sensory neurons protrude through nanoscale pores in the cuticle, while those of other sensory neurons are embedded in specialized sheets of cuticle. Both types of cuticle structure are produced by glial cells that wrap the sensory neuron endings. One of these glial cells offers a remarkable example of developmentally programmed aECM remodeling: in juveniles of both sexes and in adult hermaphrodites it produces a cuticle sheet, but in adult males it produces a cuticle pore. This represents a discrete aECM remodeling event that occurs at a defined developmental stage without any major cell rearrangements. Preliminary data show that this aECM remodeling event is accompanied by a switch in gene expression in the glial cell. This includes expression of GRL-18, a novel class of aECM component that forms nanoscale rings in the cuticle. These observations leads to the hypothesis that a developmentally regulated switch in gene expression induces remodeling of aECM to form a nanoscale pore. To test this hypothesis, this project will (Aim 1) use mutant analysis and transcriptional profiling to define the gene expression switch that accompanies aECM remodeling; (Aim 2) determine how a novel developmentally regulated protein (GRL-18) contributes to aECM structure; and (Aim 3) test if changes in expression of GRL-18 and co-regulated genes are sufficient to remodel aECM into a nanoscale pore.

摘要 顶端细胞外基质（aECM）覆盖每个器官的外表面，形成屏障 有机体和环境之间的联系。虽然它在历史上被视为一个静态层， 最近发现aECM在整个发育过程中是动态的，并且在细胞之间高度变化。 类型它在塑造器官形态发生和调节细胞活性中起重要作用。识别 因此，控制aECM组成和结构的调节机制对于 了解其在发展中的作用。此外，由于aECM是高度可及的， 潜在的操纵它靶向输送治疗或在组织工程。主要 研究aECM重塑的障碍是aECM的变化难以可视化， 在涉及复杂细胞重排的高度动态过程中进行体内研究。这 项目通过使用开发性编程aECM的创新模型克服了这些障碍 重塑初步的数据导致了这样的假设，即aECM结构是一个离散的模块化特征， 细胞身份，类似于神经元中的神经递质类型，而不是硬度/密度的连续体。 梭线虫的角质层是一种aECM，在动物与其环境之间形成屏障。在 为了直接进入外界环境，一些感觉神经元的纤毛末梢突出， 通过表皮上的纳米级孔隙，而其他感觉神经元的神经元则嵌入在 特殊的角质层这两种类型的角质层结构是由神经胶质细胞产生的， 感觉神经元末端。其中一个神经胶质细胞提供了一个显著的例子， 程序性aECM重塑：在两性青少年和成年两性人中，它产生一种 角质层片，但在成年男性它产生角质层孔。这代表了离散的aECM重塑 发生在确定的发育阶段的事件，没有任何主要的细胞重排。初步 数据显示，这种aECM重塑事件伴随着神经胶质细胞中基因表达的转换， cell.这包括GRL-18的表达，GRL-18是一类新的ECM成分， 在角质层。这些观察结果导致了一个假设，即发育调节的开关， 基因表达诱导aECM重塑以形成纳米级孔。 为了验证这一假设，本项目将（目标1）使用突变分析和转录谱分析， 定义伴随aECM重塑的基因表达开关;（目的2）确定新的 发育调节蛋白（GRL-18）有助于aECM结构;以及（目的3）测试是否改变 GRL-18和共调节基因的表达足以将aECM重塑成纳米级孔。