This project will train a new scientist specialising in EB research as they achieve their PhD by studying ways to reduce EB symptoms at a cellular level. 

Head shot of a man looking at the camera.

 Dr Rognoni works at the Blizard Institute (QMUL) and will supervise a PhD student to carry out this work on JEB skin cells. Substances already exist to stop the damaging effects of a specific protein, called integrin αvβ6 (alpha five beta six), which appears to contribute to the inflammation, scarring and slow wound healing in EB skin. Skin cells with the genetic change that causes JEB will be grown in layers as a model of JEB skin, so these substances can be tested to see if they reduce inflammation and improve skin repair. The results could be relevant for other types of EB as well, because integrin αvβ6 is present in all types of EB.

 

Contents:

 

About our funding:

Research leader Dr Emanuel Rognoni
Institution Queen Mary University of London, Faculty of Medicine and Dentistry, Blizard Institute
Type of EB JEB
Patient involvement No
Funding amount £139,962
Project length Non-clinical PhD studentship - 4 years
Start date TBC 2024
DEBRA internal ID GR000049

 

Latest progress summary:

Due 2025.

 

About our researchers:

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.

 

Why this research is important:

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

 

Researcher's abstract:

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.

 

Researcher’s progress update:

Due 2025.