Linking prolonged oxidative stress to chronic inflammation in interstitial cystitis/bladder pain syndrome

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory disease of the urinary bladder. Typical clinical signs of IC/BPS include discomfort and pain, increased urinary frequency, urgency, and nocturia, all of which negatively affect patients’ occupational and social quality of life. The disease represents an enormous financial burden for those affected and for the economy as a whole. The discovery of novel, more optimal therapeutics, and reliable disease biomarkers could contribute to earlier diagnosis, improve patients’ quality of life, and reduce the social and health-economic burden of the disease. In order to achieve this, the exact mechanisms of the development and progression of IC/BPS need to be studied and described. Different studies have identified urothelial cells of the bladder as the key effector cells in the pathobiology of IC/BPS. Damaged urothelial cells, and activation of their own immune response, are considered critical events contributing to a persistent inflammation characteristic of IC/BPS. Recent studies have found that oxidative stress resulting from either increased production of reactive oxygen species (ROS) or inadequate capacity of the antioxidant defense system is also a feature of IC/BPS. However, the exact association and molecular mechanisms linking persistent low-level oxidative stress to the urothelial cell immune response and chronic inflammation in IC/BPS have not been explored before. Thus, the main goal of this project is to explore the cellular and molecular mechanisms of the interplay between persistent oxidative stress and unresolved inflammatory process in IC/BPS, focusing on urothelial cells. The results of the project will critically improve current knowledge of disease pathobiology, identify new targets for therapeutic intervention, and propose novel disease biomarkers. To achieve our goal, we will use an integrated approach employing advanced large-scale and high-resolution techniques, such as bulk and single cell RNA sequencing, clinical data and material from patients, in vitro cell culture models, molecular and microscopic techniques, and functional assays. We will provide original information and key insights into the molecular- and cell-driven mechanisms of the pathobiology of the disease, identify potential disease biomarkers (e.g., circular cell-free mitochondrial DNA, ROS, and inflammatory mediators) in IC/BPS that could be measured in urine or serum samples, provide original information that will explain the molecular mechanisms of how oxidative stress is linked to chronic inflammation, and propose possible therapeutic targets that could be modulated to break this vicious cycle. Multi-target drug candidates with anti-inflammatory and antioxidant properties might be used as a safer and more effective alternative in IC/BPS. Altogether, we will create unique and novel biological data source in IC/BPS for: 1) better understanding of the mechanisms and pathways leading to development of the disease, 2) discovery of novel disease biomarkers and therapeutic targets/drug candidates to block chronic inflammation with possible long-term effect, and 3) development of further functional, translational and clinical studies. Ultimately, our research proposal aims to accomplish an important step forward to diminish the personal, societal and health-economic burdens of IC/BPS.