Epithelial apical membrane polarization, morphogenesis, and regulation of gene expression

上皮顶膜极化、形态发生和基因表达调控

基本信息

批准号：
BB/X000575/1
负责人：
Karl Matter
金额：
$ 88.28万
依托单位：
University 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%2FX000575%2F1
关键词：
Epithelial apical membrane polarization morphogenesis

项目摘要

Epithelia are sheets of cells that line our bodies and internal surfaces such as the intestine and the kidney, as well as the front and back of the eye. A. All our organs require epithelial cells for normal functioning and, in most of them, they are the main functional cell type. For example, in the intestine they support digestion and transport of nutrients from the intestinal lumen to the underlying blood stream. In other tissues, epithelia have crucial support functions. An example is the retinal pigment epithelium at the back of the eye, which provides vital support functions for photoreceptors, the cells that sense light. Without a healthy retinal pigment epithelium, photoreceptors stop to function and die. We are interested in the processes that determine how such epithelia form and are maintained throughout life, and how deregulation of such processes leads to tissue degeneration and different types of diseases. Such knowledge is important for diseases associated with aging, in which normal tissue often function often declines due to defects in epithelia. To be able to form cell sheets and to function correctly, epithelial cells need to adhere to each other, and they need to polarize by forming distinct cell surface domains that have different compositions and functional roles. A typical epithelial cell has a basal domain with which it interacts with the underlying tissue, a lateral domain with which it adheres to its neighbours enabling sheet formation, and an apical domain that faces the outside of an epithelium. The apical and lateral domains are separated by a large protein complex called tight junctions. Tight junctions support barrier formation by making cells adhere to each other and by functioning as regulatory centres that guide cell proliferation, behaviour, polarization, and tissue formation. Defects in epithelial cell polarization occur in many serious diseases that can be inherited or induced by aging, environmental factors, or infections. Here, we are focusing on a mechanism that we have recently discovered to regulate cells polarization and cell shape. We have discovered this mechanism in cells in culture, but it is also essential in tissues as its disruption in the retinal pigment epithelium leads to malfunction and retinal degeneration. One of the main effects of the pathway is on the regulation of the cytoskeleton, a dynamic structure formed by filaments and motor proteins that generate mechanical forces. Our pilot studies suggest a model in which activation of the mechanism at the apical domain induces a signalling cascade that leads to remodelling of mechanical forces across the cell, promoting cell polarisation and shape changes, as well as regulating expression of genes that are involved in cell proliferation and function. Our first aim is to determine how this mechanism regulates mechanical forces across epithelial cells and to test the hypothesis using approaches to manipulate opposing forces. Our second aim is to determine the underlying molecular mechanisms by which this mechanism regulates cell proliferation and gene expression in cell culture models as well as the retinal pigment epithelium in mice. We expect our results to establish new principles that govern how epithelia form and how deregulation of the underlying biological mechanisms leads to tissue malfunction and disease. The expected knowledge will support the development of new approaches to repair malfunctioning tissues in acute diseases such as infections and cancer, as well as chronic and age-related diseases that affect the eye and other organs.

上皮是在我们的身体和内部表面（例如肠和肾脏）以及眼睛的前后表面的细胞片。答：我们所有的器官都需要上皮细胞来进行正常功能，在大多数人中，它们是主要功能性细胞类型。例如，在肠道中，它们支持从肠道流明到潜在的血液的消化和运输。在其他组织中，上皮具有至关重要的支持功能。一个例子是眼睛背面的视网膜色素上皮，它为感光体提供了重要的支持功能，即感知光的细胞。如果没有健康的视网膜色素上皮，感光器就停止起作用并死亡。我们对确定这种上皮的形成方式和维持在整个生命的过程以及这种过程的放松管制如何导致组织变性和不同类型的疾病的过程感兴趣。这种知识对于与衰老相关的疾病很重要，在与衰老有关的疾病中，正常组织通常由于上皮缺陷而经常下降。为了能够形成细胞表并正确功能，上皮细胞需要彼此粘附，并且需要通过形成具有不同组成和功能角色的不同细胞表面域来极化。一个典型的上皮细胞具有基础结构域，它与下面的组织相互作用，它的侧向结构域粘附在其邻居上，使薄片形成，而顶部域则面向上皮的外部。顶端和侧域被称为紧密连接的大蛋白质复合物分离。紧密的连接通过使细胞彼此粘附并充当指导细胞增殖，行为，极化和组织形成的调节中心来支持屏障的形成。上皮细胞极化中的缺陷发生在许多严重的疾病中，这些疾病可能因老化，环境因素或感染而遗传或诱发。在这里，我们关注的是一种机制，我们最近发现了调节细胞极化和细胞形状的机制。我们已经在培养细胞中发现了这种机制，但是它在组织中也是必不可少的，因为它在视网膜色素上皮中的破坏会导致故障和视网膜变性。该途径的主要影响之一是对细胞骨架的调节，这是一种动态结构，由细丝和产生机械力的运动蛋白形成。我们的试点研究提出了一个模型，在该模型中，顶端结构域的机制激活会诱导信号传导级联反应，从而导致整个细胞的机械力重塑，从而促进细胞极化和形状变化，并调节与细胞增殖和功能有关的基因表达。我们的第一个目的是确定该机制如何调节上皮细胞的机械力，并使用操纵对立力的方法检验假设。我们的第二个目的是确定这种机制在细胞培养模型中调节细胞增殖和基因表达以及小鼠的视网膜色素上皮的基本机制。我们预计我们的结果将建立新的原则，以控制上皮症的形成以及对基本生物学机制的放松管制如何导致组织故障和疾病。预期知识将支持开发新方法，以修复急性疾病（例如感染和癌症）以及影响眼睛和其他器官的慢性和年龄相关疾病。