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Regulation of epithelial apical membrane differentiation and function

上皮顶膜分化和功能的调节

基本信息

批准号：
BB/L007584/1
负责人：
Karl Matter
金额：
$ 61.14万
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：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FL007584%2F1
关键词：
Regulation epithelial apical membrane differentiation

项目摘要

Epithelia are continuous layers of cells that delineate our tissues and organs. Individual epithelial cells interact with each other via molecular complexes that mediate adhesion but also function as sensors that transmit information about the presence or absence of neighbouring cells to the cell interior. Integrity of epithelia is important for our organs to develop and function normally, and to protect us from our environment. For example, breaches in epithelial layers such as the skin or in the lining of the intestine can lead to serious infections and can occur due to chronic inflammations or acute infections by viruses and bacteria. Similarly, a characteristic of cancer cells is that they have lost the capability to sense the presence of neighbouring cells or how tightly they are packed, and hence continue to proliferate and migrate on top of their neighbours. Epithelia are polarised, which means they have two cell surface domains that have different compositions and functions. The cell surface that faces the outside world or the internal lumen in our organs is called the apical cell surface. This apical domain often forms a highly specialised structure that mediates organ specific functions, such as digestion and nutrient absorption in the intestine or supportive functions for the cells that sense light in our eyes. Here, we propose to investigate a molecular mechanism that drives the formation of such specialised apical membranes in intestinal and retinal epithelial cells. This pathway is based on signalling proteins that we have recently identified and for which we have evidence that they form a mechanism that may also inhibit the function of proteins that have been linked to tumorigenesis and cancer by stimulating cells to differentiate and form tightly packed cellular sheets. Knowledge of how epithelial cells differentiate to mediate organ specific functions and how such pathways inhibit mechanisms that can lead to cancer is important to understand how tissues behave in disease. Epithelial dysfunction has been linked to many diseases such as cancer, chronic inflammations in the intestine, and inherited and age-related diseases that lead to blindness. The expected results will help us to think of new ways how we can treat such diseases that lead to epithelial degeneration and cancer.

上皮是连续的细胞层，勾画出我们的组织和器官。单个上皮细胞通过介导粘附的分子复合物相互作用，同时也充当传感器，将有关邻近细胞存在或不存在的信息传递到细胞内部。上皮细胞的完整性对于我们器官的正常发育和功能以及保护我们免受环境影响非常重要。例如，皮肤等上皮层或肠道内壁的破损可能导致严重感染，并且可能由于慢性炎症或病毒和细菌的急性感染而发生。同样，癌细胞的一个特征是它们失去了感知邻近细胞的存在或它们排列的紧密程度的能力，因此继续增殖并迁移到邻近细胞的顶部。上皮是极化的，这意味着它们具有两个具有不同组成和功能的细胞表面域。面向外界或我们器官内腔的细胞表面称为顶端细胞表面。这个顶端区域通常形成高度专业化的结构，介导器官特定功能，例如肠道中的消化和营养吸收或对我们眼睛中感知光的细胞的支持功能。在这里，我们建议研究驱动肠和视网膜上皮细胞中这种特殊顶膜形成的分子机制。该途径基于我们最近鉴定的信号蛋白，并且我们有证据表明它们形成了一种机制，该机制也可能通过刺激细胞分化和形成紧密堆积的细胞片来抑制与肿瘤发生和癌症相关的蛋白质的功能。了解上皮细胞如何分化以介导器官特异性功能以及这些途径如何抑制可能导致癌症的机制对于了解组织在疾病中的行为非常重要。上皮功能障碍与许多疾病有关，例如癌症、肠道慢性炎症以及导致失明的遗传性和年龄相关疾病。预期的结果将帮助我们思考如何治疗导致上皮变性和癌症的疾病的新方法。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Small and large intestine express a truncated Dab1 isoform that assembles in cell-cell junctions and co-localizes with proteins involved in endocytosis.

小肠和大肠表达截短的 Dab1 亚型，该亚型在细胞-细胞连接处组装，并与参与内吞作用的蛋白质共定位。

DOI：
10.1016/j.bbamem.2018.02.014
发表时间：
2018
期刊：
Biochimica et biophysica acta. Biomembranes
影响因子：
0
作者：
Vázquez-Carretero MD
通讯作者：
Vázquez-Carretero MD

An apical MRCK-driven morphogenetic pathway controls epithelial polarity.

DOI：
10.1038/ncb3592
发表时间：
2017-09
期刊：
Nature cell biology
影响因子：
21.3
作者：
Zihni C;Vlassaks E;Terry S;Carlton J;Leung TKC;Olson M;Pichaud F;Balda MS;Matter K
通讯作者：
Matter K

ZO-1 controls endothelial adherens junctions, cell-cell tension, angiogenesis, and barrier formation.

DOI：
10.1083/jcb.201404140
发表时间：
2015-03-16
期刊：
The Journal of cell biology
影响因子：
0
作者：
Tornavaca O;Chia M;Dufton N;Almagro LO;Conway DE;Randi AM;Schwartz MA;Matter K;Balda MS
通讯作者：
Balda MS

RhoGTPase signalling at epithelial tight junctions: Bridging the GAP between polarity and cancer.

DOI：
10.1016/j.biocel.2015.02.020
发表时间：
2015-07
期刊：
The international journal of biochemistry & cell biology
影响因子：
0
作者：
Zihni C;Terry SJ
通讯作者：
Terry SJ

The tumour suppressor DLC2 ensures mitotic fidelity by coordinating spindle positioning and cell-cell adhesion.

DOI：
10.1038/ncomms6826
发表时间：
2014-12-18
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Vitiello, Elisa;Ferreira, Jorge G.;Maiato, Helder;Balda, Maria S.;Matter, Karl
通讯作者：
Matter, Karl