The epithelial junction protein MarvelD3 in cell proliferation and migration

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Here we propose experiments to investigate a new mechanism that, based on our unpublished results, links adhesion between cells to the regulation of cell migration and proliferation.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.

Epithelial cells adhere to each other via junctional complexes, enabling them to form cellular barriers that separate different tissues and body compartments. These adhesive complexes transmit signals to the cell interior to guide gene expression and cellular processes such as proliferation and migration. Tight junctions are one type of intercellular junctions and restrict paracellular permeability. They are also thought to signal to the cell interior and several signal transduction pathways have been identified that are regulated by tight junctions. However, we know little about how plasma membrane components of tight junctions contribute to the regulation of the junction-associated signalling mechanisms and about the importance of such mechanisms for developmental processes. This proposal focuses on MarvelD3, a recently discovered transmembrane protein of tight junctions. Our preliminary data indicate that MarvelD3 signalling regulates cell proliferation and migration. At least in part, this involves regulation of specific signal transduction mechanisms. Our aims are to identify molecular mechanisms by which MarvelD3 signals, to determine the role of MarvelD3 in a developmental model, and to test whether MarvelD3 signalling can be targeted to improve the quality of corneas donated for transplantation. The expected results will be important for the understanding of how cell-cell adhesion guides epithelial behaviour and to develop possible therapeutic strategies.

Who will benefit from this research?

The immediate beneficiaries will be scientists working in allied fields at Universities as well as in industry. This includes scientists working in areas such as tissue engineering, infections and wound repair, as well as chronic inflammation and cancer biology. The development of new techniques to enhance the numbers of corneas of sufficient qualities for transplantation has many beneficiaries both nationally and internationally. Corneas for sufficient quality for transplantation are limited and will become even more limited due to our increasing age and medical treatments that affect the quality of donated corneas (e.g., laser treatments). Hence, beneficiaries will also be medical scientists, surgeons and patients, as well as the NHS and thereby the general public.


How will they benefit from this research?

The research will benefit allied scientists by providing them with the molecular details of a new mechanism that links cell-cell adhesion to the regulation of cell proliferation and migration that they can then test in their respective model systems. Translational scientists will benefit in a similar way. For example, scientists interested in carcinomas and tumour spreading will be able to build on our research to exploit the identified molecular pathway to suppress metastasis and tumour proliferation. In our own research environment, these results will benefit researchers and clinicians who work on corneal transplantation as they will be able to adapt techniques and tools developed in the proposal for clinical purposes. The research will also help to target proliferative conditions of the retinal pigment epithelium. A better accessibility of transplants with more endothelial cells will improve patients lives as waiting times will be shorter and transplant lifetime longer. This will have a positive impact on NHS services, reduce costs, and, thereby, benefit the taxpayer. Treating patients with better corneas will in the long term have a positive impact on their wellbeing and associated social costs, and will therefore also benefit society as a whole. The project will also involve training of a postdoctoral fellow and a technician in laboratory techniques that can benefit the private sector as well as public services through the NHS (e.g., preparation and evaluation of corneal transplants).

The expected results are likely to start to benefit other scientists within the lifetime of this grant, and we hope to be in the position to plan strategies how techniques developed for corneal transplants can be developed for clinical applications by the end of this grant.