TRPM2-mediated immune activation initiates radiation-induced loss of oral function

Project Summary: Radiation-Induced Oral Mucositis (RIOM) is a common and painful side effect of radiation therapy in head and neck cancer treatment. RIOM affects the oral mucosa, leading to inflammation, ulceration, and a significant reduction in the patient’s quality of life. Current treatments are palliative and do not prevent RIOM development. TRPM2 (transient receptor potential melastatin 2), a calcium-permeable channel, is implicated in oxidative stress and inflammation, processes involved in RIOM. However, its role in RIOM is not studied till date. Our goal is to investigate the role of TRPM2 in the development of RIOM and evaluate the potential of TRPM2 inhibition as a preventative treatment. Using human cells and mouse models, our preliminary data showed that TRPM2 activities are increased in oral keratinocytes during RIOM and is involved in activation of the inflammasome pathway and cellular toxicity. Moreover, pharmacological inhibition of TRPM2 prevented development of RIOM in mouse models. Accordingly, our central hypothesis is that radiation-induced ROS initiates TRPM2 activation and Ca2+ entry in oral keratinocytes leading to activation of the inflammasome pathway and subsequent cell death and immune response, thereby contributing to RIOM. Our objectives of this proposal include 1) understanding how TRPM2 influences the onset and progression of Radiation-Induced Oral Mucositis (RIOM); 2) investigating how calcium influx through TRPM2 influences the inflammasome pathway to control immune and inflammatory responses during RIOM and 3) assess whether inhibiting TRPM2/inflammasome can be a viable strategy for preventing or reducing the severity of RIOM without affecting cancer therapy. The research is significant for uncovering TRPM2's role in RIOM and could lead to novel therapeutic approaches for both RIOM and oral mucositis from other treatments.. Public Relevance This study tackles a critical clinical challenge: Radiation-Induced Oral Mucositis (RIOM), a painful and debilitating complication of radiation therapy in patients with head and neck cancer. RIOM exacerbates the overall burden of cancer by diminishing treatment success, increasing healthcare costs, and severely impacting quality of life. To improve patient outcomes, it is essential to fully understand the pathophysiology of RIOM and explore potential therapeutic strategies. This research aims to uncover the molecular mechanisms driving cell death and ulceration in oral mucosal tissues post-radiation, paving the way for advancements in oral and dental care. By identifying novel therapeutic targets, the study holds promise for mitigating the effects of oral mucositis.