Mechanisms of ventral body wall closure

腹侧体壁闭合机制

• 批准号: BB/W01730X/1
• 负责人: Jeremy Green
• 金额: $ 77.75万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW01730X%2F1
• 关键词: Mechanisms; ventral; body; wall; closure

The abdomen (belly) of a baby is formed in the womb by the wrapping of the internal organs, first by a thin layer of so-called mesoderm and ectoderm ("primary body wall") and then by muscle and connective tissue ("secondary body wall"). How the secondary wall replaces the primary is not understood, but a snug fit is maintained throughout the process because the internal organs are growing rapidly at the same time. About one in 2000 babies are born with a defect in the abdominal wall, which most often presents clinically as a hole in the abdomen through which parts of the gut and sometimes the liver protrude (herniate). The causes of abdominal wall defects are also not well understood, in part because the basic embryology involved has not been studied in a detailed quantitative way. In the proposed project, we will use the mouse embryo, in which abdominal wall closure is very similar to that in humans, as a model to understand the details of growth, reshaping and physical forces that must work together to enable the secondary body wall to form. We will first make a 'growth atlas' of the abdominal wall to determine how the entire process coordinates replacement of the primary wall by the secondary wall while containing the internal organs. To link the anatomical changes with our understanding of cell biology, we will look in fixed specimens at the cells that make up all the tissues to see how the growth and re-shaping are achieved by cell multiplication, rearrangement, and size change, and take pieces of living embryonic tissue in which cells are fluorescently labelled so that we can microscopically observe these cell behaviours individually. We will compare embryos from healthy mice with those from mouse mutants known to have frequent abdominal closure defects to see which cellular processes are abnormal so as to cause abdominal defects. Finally, we will test the idea that the abdominal wall growth is triggered and coordinated by mechanical tension, exerted by primary body wall narrowing and pulling on the secondary body wall and by expansion of the growing internal organs. To do this, we will map tension across the growing abdominal wall and see if it correlates in space or time with cell proliferation and make small incisions to relieve local tension, investigating whether this reduces local proliferation. We will also investigate a molecular signalling pathway, known as Yap/Taz, that is known in other situations to stimulate cell proliferation in response to tension, and ask if it is present, active, and necessary for abdominal wall growth. Together the investigations in this project will provide an integrated understanding of abdominal wall closure, establishing the basic biology and elucidating ways in which birth defects might occur.

婴儿的腹部（腹部）在子宫中由内部器官的包裹形成，首先是一层薄薄的所谓的中胚层和外胚层（“初级体壁”），然后是肌肉和结缔组织（“次级体壁”）。次生壁如何取代初级壁尚不清楚，但在整个过程中保持紧密配合，因为内部器官同时快速生长。大约每2000个婴儿中就有一个出生时腹壁有缺陷，临床上最常见的表现是腹部有一个洞，部分肠道和有时肝脏通过这个洞突出（疝出）。腹壁缺损的原因也没有得到很好的理解，部分原因是涉及的基本胚胎学尚未进行详细的定量研究。在拟议的项目中，我们将使用小鼠胚胎，其中腹壁闭合与人类非常相似，作为模型来了解生长，重塑和物理力量的细节，这些力量必须共同作用才能形成次级体壁。我们将首先制作一个腹壁的“生长图谱”，以确定整个过程如何协调次级壁取代初级壁，同时包含内部器官。为了将解剖学变化与我们对细胞生物学的理解联系起来，我们将在固定的标本中观察组成所有组织的细胞，以了解细胞的增殖、重排和大小变化是如何实现生长和重塑的，并取下活的胚胎组织，其中的细胞被荧光标记，以便我们可以在显微镜下单独观察这些细胞的行为。我们将比较来自健康小鼠的胚胎与已知具有频繁腹部闭合缺陷的突变小鼠的胚胎，以观察哪些细胞过程异常从而导致腹部缺陷。最后，我们将测试的想法，腹壁的增长是由机械张力触发和协调，施加的主要体壁缩小和拉动二级体壁和扩张的内部器官的增长。为了做到这一点，我们将绘制整个生长的腹壁的张力，看看它是否在空间或时间上与细胞增殖相关，并制作小切口来缓解局部张力，研究这是否会减少局部增殖。我们还将研究一种分子信号通路，称为雅普/塔兹，这是已知的在其他情况下，刺激细胞增殖的张力，并询问它是否存在，活跃，腹壁生长所必需的。本项目的研究将提供对腹壁闭合的综合理解，建立基础生物学并阐明出生缺陷可能发生的方式。