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The epithelial junction protein MarvelD3 in cell proliferation and migration

上皮连接蛋白MarvelD3在细胞增殖和迁移中的作用

基本信息

批准号：
BB/J015032/1
负责人：
Karl Matter
金额：
$ 63.17万
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：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FJ015032%2F1
关键词：
epithelial junction protein MarvelD3 cell

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 environment, such as 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 and hence continue to proliferate and migrate on top of their neighbours, or leave their tissue of origin by migrating to and invading other tissues and organs and, thereby form metastasis. On the other hand, in many adult tissues cells do no longer multiply and this can lead to reduced cell numbers and loss of normal organ function due to age or tissue damage. It is thus of fundamental importance to understand how cells in a tissue adhere to and recognise each other, how this influences their proliferative and migratory properties, and how we can exploit such mechanisms to manipulate their behaviour to address medical problems. Here we propose experiments to investigate a new mechanism that, based on our unpublished results, links adhesion between cells to the regulation of cell migration and proliferation. Our first aim is to determine how this mechanism works during epithelial repair processes and, our second aim, how it contributes to normal development of epithelial tissues. Our third aim is to use this information and address a medical problem that is caused by a lack of cell proliferation. The cornea is a tissue at the front of the eye that is required for normal vision. It is formed by an epithelium on the outside and a layer of cells on the inside, called corneal endothelium. As cells in the corneal endothelium do normally not proliferate and regenerate, their numbers decline with age or when the cornea gets damaged. If their numbers are too low, the cornea loses its transparency resulting in a loss of vision. This seriously affects the availability and quality of human corneas for transplantation that are donated to treat patients with damage to the surface of the eye. Hence, we propose experiments to test whether the here-identified mechanism can be exploited to enhance the quality of donated human corneas and thereby enhance the number of corneas that are adequate for transplantation. Knowledge of how cells sense their neighbours and transmit such information to the cell interior, and how we can manipulate such processes has a wide range of potential applications apart from the one that we will test here. The expected results will help us to think of new ways to aid wound repair after surgery and to treat devastating diseases such as chronic inflammations, certain infections 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，将有关环境的信息（例如邻近细胞的存在或不存在）传输到细胞内部。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存在的能力，因此继续增殖并在邻近细胞的上方迁移，或者通过迁移和侵入其他组织和器官而离开其来源组织，从而形成转移。另一方面，在许多成体组织中，细胞不再繁殖，这可能导致细胞数量减少，并因年龄或组织损伤而丧失正常器官功能。因此，了解组织中的细胞如何粘附和识别彼此、这如何影响它们的增殖和迁移特性以及我们如何利用这些机制来操纵它们的行为来解决医疗问题至关重要。在这里，我们提出实验来研究一种新机制，根据我们未发表的结果，将细胞之间的粘附与细胞迁移和增殖的调节联系起来。我们的第一个目标是确定这种机制在上皮修复过程中如何发挥作用，我们的第二个目标是确定它如何促进上皮组织的正常发育。我们的第三个目标是利用这些信息来解决因细胞增殖缺乏而引起的医学问题。角膜是眼睛前部的组织，是正常视力所必需的。它由外部的上皮和内部的一层细胞形成，称为角膜内皮。由于角膜内皮细胞通常不会增殖和再生，因此它们的数量会随着年龄的增长或角膜受损而减少。如果它们的数量太低，角膜就会失去透明度，导致视力丧失。这严重影响了用于移植的人类角膜的可用性和质量，这些角膜是为治疗眼睛表面损伤的患者而捐赠的。因此，我们提出实验来测试是否可以利用此处确定的机制来提高捐赠的人类角膜的质量，从而增加足以移植的角膜的数量。除了我们将在这里测试的应用之外，了解细胞如何感知其邻居并将此类信息传输到细胞内部，以及我们如何操纵这些过程具有广泛的潜在应用。预期的结果将帮助我们寻找新的方法来帮助手术后伤口修复以及治疗慢性炎症、某些感染和癌症等破坏性疾病。

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）

Global cell-by-cell evaluation of endothelial viability after two methods of graft preparation in Descemet membrane endothelial keratoplasty.

DOI：
10.1136/bjophthalmol-2015-307534
发表时间：
2016-04
期刊：
The British journal of ophthalmology
影响因子：
0
作者：
Bhogal M;Balda MS;Matter K;Allan BD
通讯作者：
Allan BD

MarvelD3 couples tight junctions to the MEKK1-JNK pathway to regulate cell behavior and survival.

DOI：
10.1083/jcb.201304115
发表时间：
2014-03-03
期刊：
The Journal of cell biology
影响因子：
0
作者：
Steed E;Elbediwy A;Vacca B;Dupasquier S;Hemkemeyer SA;Suddason T;Costa AC;Beaudry JB;Zihni C;Gallagher E;Pierreux CE;Balda MS;Matter K
通讯作者：
Matter K

Stimulation of cortical myosin phosphorylation by p114RhoGEF drives cell migration and tumor cell invasion.

P114RHOGEF刺激皮质肌球蛋白磷酸化驱动细胞迁移和肿瘤细胞侵袭。