A single protein, Notch3, can either help heal damaged gum tissue or drive the inflammation that destroys it, depending on the circumstances. This dual role matters because chronic gum disease—periodontitis—affects nearly half of UK adults and is linked to tooth loss, heart problems, and diabetes. Scientists do not yet understand why the same molecular switch promotes repair in one context and pathology in another. This project will map that decision-making process by tracking Notch3-expressing cells in healthy and diseased mouse gums, analysing their genetic activity (RNA-seq), epigenetic marks (ChIP-seq), and the bacterial communities in saliva. The team will also use genetically engineered mice to activate or block Notch3 and observe the consequences. If successful, the research could reveal precisely when and how to nudge Notch3 toward healing and away from harm. That knowledge might lead to new treatments for periodontitis that modulate this single pathway, or to biomaterials that encourage regeneration rather than scarring. The project is fundamentally curiosity-driven—it asks how a core signalling pathway governs tissue behaviour—but the answers could eventually reshape how dentists and doctors manage chronic oral inflammation.
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Notch signaling is a fundamental biological pathway that regulates cell fate, tissue homeostasis, and regeneration across diverse tissues. In oral tissues, Notch3—a key receptor in this pathway—has been identified as a critical player in maintaining cellular equilibrium and responding to injury. However, its role appears dualistic, contributing to tissue regeneration under some conditions and exacerbating pathological changes under others, such as in periodontal disease and oral inflammation. Understanding this dual nature is essential for developing effective therapeutic strategies. This project seeks to explore the precise role of Notch3 populations in oral tissues, aiming to clarify whether they act as "friends" by promoting repair and homeostasis, or as "foes" by driving disease progression. To achieve this, we will use cutting-edge techniques to study how Notch3-expressing cells behave in both healthy and diseased conditions. This work will involve multiple computational analysis, including RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) of gingival Notch3+ cells, as well as metagenomic profiling of saliva, to uncover the genetic, epigenetic, and bacterial mechanisms underlying their function in health and disease. Furthermore, we will use cutting-edge lineage tracing techniques to study how Notch3-expressing cells behave, as well as genetic engineered mice to investigate the impact of functional modulation (activation/inhibition) of Notch3 in both healthy and diseased conditions. This comprehensive approach will uncover the mechanisms underlying the function of Notch3 in oral tissues biology. By addressing this challenge, the research aims to uncover actionable insights into the regulation of oral health and the progression of infectious-inflammatory diseases like periodontitis. These findings could pave the way for novel therapies that modulate Notch3 activity, improving outcomes for patients with chronic oral conditions. The project aligns with the Biotechnology and Biological Sciences Research Council's (BBSRC) long-term priorities by advancing understanding in tissue homeostasis and regeneration, a critical area for improving public health. It also holds potential applications in developing biomaterials and precision medicine approaches tailored to oral health care. Additionally, our work will enable the introduction of novel mouse models to the United Kingdom, that could be further used by collaborators interested in the Notch3 pathway. This research promises to contribute significantly to both fundamental biological knowledge and translational innovation in dentistry and regenerative medicine
Graham Stafford (Co-Investigator)Sheila Francis (Co-Investigator)Vitor De Carvalho Moreno Das Neves (Principal Investigator)Willian Da Silveira (Co-Investigator)
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