PhD: improving skin repair in JEB

Researchers have confirmed that αvβ6 integrin is present in blisters in JEB patient skin biopsies and in their model. They have blocked αvβ6 integrin function in the model and showed that this improves skin health and repair with less inflammation and reduced blistering.

Lead researcher:

Dr Emanuel Rognoni is a Senior Lecturer at the Blizard Institute. During his PhD he focused on the EB subtype Kindler Syndrome where he revealed a novel function of the integrin binding protein Kindlin-1 for epithelial stem cell homeostasis by promoting αvβ6 integrin-mediated transforming growth factor-β (TGFβ) activation and epithelial Wnt signalling. During his postdoc he further specialized in skin research, investigating how different dermal fibroblast subpopulations organize and influence each other during development and wound healing in Prof Fiona Watt’s lab (KCL). Using genome-wide sequencing technologies, innovative 2D/3D culture platforms and skin transgenic/disease models, his group at QMUL is now uncovering the molecular mechanisms and implications of fibroblast heterogeneity in skin health, regeneration and disease.

Co-researchers:

Dr Matthew Caley is a Senior Lecturer in Cell Biology at the Blizard Institute with more than a decade of experience in skin research, matrix biology and generating in vitro skin models. He is active within the British and European skin research communities, a committee member of the British Society for Investigative Dermatology (BSID) and a founder of the national Skin Microbiome in Healthy Ageing (SMiHA) research network. His group use models of skin to understand the molecular biology of skin ageing, rare genetic skin diseases and skin cancer. His special focus has been on laminin 332 and how this protein is far more than just a structural protein.

Prof John Marshall is a Professor of Tumour Biology whose research focuses on the function of cell adhesion receptors, integrins, in tumour cell invasion with more than 130 publications. He is a leading expert in dissecting the function and therapeutic potential of the epithelial cell specific integrin αvβ6 which is highly upregulated during tissue remodelling in chronic wounds and cancer. His research has involved multiple industry collaborations and clinical trials.

“Our goal is to improve the skin of JEB patients, improve wound healing and therefore reduce the risk of infections that can lead to sepsis and premature death.”

– Dr Rognoni

Grant title: Improving skin regeneration in JEB by targeting the integrin αvβ6.

Junctional epidermolysis bullosa (JEB) is a rare genetic skin disease leading to widespread blistering and impaired wound healing. This is caused by loss of vital proteins that anchor the outer skin layer to the rest of the body. The most severe form, JEB severe, is caused by loss of laminin-332 function a key component of the skin anchoring structure. Patients with JEB suffer from failure to thrive, poor wound healing, severe skin pain and high risk of blood poisoning (sepsis). Babies diagnosed with JEB severe nearly all die before their second birthday and so far there are no effective treatments to halt or cure this deadly skin disease. We have identified that the transforming growth factor beta (TGFβ) signalling pathway is overactivated in JEB skin. We believe this is due mostly to the high levels of integrin αvβ6, a major regulator of TGFβ signalling in skin, which is also observed in chronic wounds, fibrosis and skin immune reactions. We will investigate the αvβ6 functions in JEB skin using our in vitro cell culture models (Aim-1&2) and use our JEB disease model to understand the role of αvβ6 in normal skin and wound healing (Aim-3). Finally, we will block integrin αvβ6 in our JEB model and study how it prevents overactivation of TGFβ and hopefully improves JEB skin repair (Aim-4). Our pre-clinical study will determine if selective targeting of αvβ6 integrin could offer novel therapeutic opportunities in JEB and potentially other EB types with deregulated αvβ6 and TGFβ signalling.

JEB is not currently curable and current treatments focus on managing the blisters, controlling infections and preventing complications. At the root of the disease is the loss of the anchoring protein laminin-332 from the skin. Our data identify that a specific cell adhesion receptor, named αvβ6 integrin, becomes highly upregulated in JEB skin, which is also observed in chronic wounds, fibrosis and aggressive tumours. αvβ6 integrin not only helps skin cells to adhere and migrate but also controls the activity of potent growth factors, including TGFβ. Overactivation of TGFβ causes wound healing defects and skin inflammation. Using our unique preclinical JEB models, we will determine the role of αvβ6 integrin in JEB skin. We will explore if blocking the function of αvβ6 integrin has the potential to improve wound healing in JEB. Targeting αvβ6 integrin may not be a curative treatment, however, our approach has the potential to treat pathological growth factor signalling such as TGFβ and support the healing of blistered skin, improving the quality of live and survival of JEB patients. Because αvβ6 integrin and TGFβ is also deregulated in multiple EB subtypes, our study will support the therapeutic development for other skin blistering diseases.

The aim of this project is to explore if targeting the specific cell adhesion receptor, named αvβ6 integrin is able to improve the skin in the genetic skin blistering disease Junctional epidermolysis bullosa (JEB). Our plan is to investigate the αvβ6 functions in JEB skin using our in vitro cell culture models (Aim-1&2) and use our JEB disease model to understand the role of αvβ6 in normal skin and wound healing (Aim-3). Finally, we will block integrin αvβ6 in our JEB model and study how it prevents overactivation of transforming growth factor beta (TGFβ) signalling pathway and improves JEB skin repair (Aim-4).

At the start of the project we recruited a very talented PhD student who immediately engaged with the project after completing all necessary training courses. Due to restructuring of the QMUL facilities we decided to priorities the in vivo experiments (Aim-3 and Aim-4). Here we started by further analysing the presence of integrin αvβ6 in wounded and unwounded skin in our JEB disease model which is particularly high in blistered skin. We also confirmed that αvβ6 integrin is also expressed in blisters in JEB patient skin biopsies. We have completed the first experiments blocking αvβ6 integrin function in our JEB disease model for two weeks and we were able to observe a considerable improvement of JEB skin health and repair. Intriguingly the JEB skin was not only less fibrotic and inflamed but also we observed a reduction in skin blisters and their severity. We are now continuing our analysis to explore how αvβ6 inhibition changes skin inflammation and improves skin health. We are particularly interested in testing more long term treatments of blocking αvβ6 integrin and how it will improve the healing of open wounds.

While in this first year the PhD student has focused on the analysis of the in vivo experiments, she has also started to explore the molecular function of integrin αvβ6 integrin (Aim-1&2) by establishing a lot of necessary experimental tools in the lab. Importantly, the PhD student has successfully submitted and passed her 9 month PhD progression viva. An important highlight for the student was to present her exciting results from her first year at one of the leading skin UK conferences in April this year, where her abstract was immediately selected for an oral presentation. Furthermore the PhD student and the PI have produced two DEBRA UK blog article (https://www.debra.org.uk/repairing-skin-cells/ and https://www.debra.org.uk/improving-eb-wound-healing/) about this project and we both have also engaged in PPI activities from other EB charities such as the CureEB family day, to further disseminate our EB research to the wider public. (From 2025 progress report.)