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Identifying innate and adaptive immune mechanisms associated with fibrosis in animal models of RDEB (Liao 1)

Project lead Dr Yanling Liao
Organisation New York Medical College, New York, USA
Partner organizations & collaborators Professor Mitchell Cairo, Associate Chair of the Department of Pediatrics & Professor of Pediatrics, Medicine, Pathology, Microbiology, Immunology, Cell Biology & Anatomy at NYMC
Project budget GBP 250,000.00 + Time only Extension
Start date / Duration 01. Jul 2020 / 48 months
Funder(s) / Co-Funder(s) DEBRA UK, DEBRA Ireland, MSAP/EBEP Recommended
Research area Symptom prevention & relief, Immunology

Project details

Short lay summary

There are two types of inflammation, the first is microbial-mediated (e.g. the presence of bacteria), and the other one is in the absence of microbial organisms, also named sterile inflammation. A defining feature of sterile inflammation is that it can often result in a chronic inflammatory process and fibrosis. Based on our preliminary preclinical studies, it is possible that patients with RDEB could be born with sterile inflammation and further be confounded by microbial-mediated inflammation because of the lack of Collagen 7. This brings into question the systemic challenges associated with EB – far more than just a problem with the skin and mucosa. Continuous and unresolved inflammation then leads to a chronic problem, fibrosis and ultimately may be linked to the development of squamous cell carcinoma. It is therefore essential to understand the mechanisms of this early inflammatory process.

The proposed studies will involve an RDEB model that lacks COL7A1 to investigate what types of immune cells infiltrate the skin under sterile conditions. The group will also look at what molecular signals induce their infiltration, how they interact with each other and with the skin microenvironment. Based on these results, they will investigate if the molecular signals can be stopped or slowed to suppress the development of chronic inflammation and fibrosis.

Elements of the two types of immune response (innate and adaptive), have both been demonstrated to play an important role in triggering fibrosis in many organ systems such as lung and liver. However, their role in chronic inflammation and fibrosis in RDEB is remains poorly understood.

The proposed studies will investigate the sequence of immune responses and their correlation with signalling transduction in the skin to understand progression and alteration of the immune response.

It is hoped that by determining the signalling pathways, this work will reveal the mechanisms that correlate with inflammation and fibrosis, identify potential targets for early intervention and development of novel and more effective immune therapies in RDEB.

More details on DEBRA UK's website.

Strategic relevance

“It has been well recognized that chronic inflammation and fibrosis contribute to squamous cell carcinoma development in patients with RDEB. The inflammatory response, which is a natural defense system in our body, is supposed to be resolved after defending infection and/or injury, yet it is not resolved in patients with RDEB. Instead, it evolves into an unwanted chronic condition in these patients. As such, our investigations will help us identify how immune cells in the skin change with time in response to changes within the dermal microenvironment. This research will help us understand the mechanism of chronic inflammation and identify novel targets for the treatment or prevention of chronic inflammation and fibrosis in patients with RDEB.” Dr Yanling Liao  

More on DEBRA UK's website


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