CURIES · Chip URInary Engineered System for modelling bladder biomechanics and disease

Urinary tract infections (UTI) are severe bacterial infections of the urinary system. Low understanding of specific bacteria-host interactions and associated disease aetiologies has led to global misuse of antibiotics driving bacterial resistance. However, relevant human modelling platforms that replicate all parameters of a physiological bladder and reciprocate infection conditions are non-existent. During infection bladder stretch-mechanisms are commandeered by opportunistic bacteria to penetrate the impermeable bladder defence, that are then not appropriately cleared by antibiotics regimens. With CURIES, we will develop microfluidic bladder-on-chip systems able to replicate the dynamic biomechanical scenarios and chemically-rich environments of the bladder epithelium; the urothelium. Without appropriate models that recapitulate organ biomechanics the emergence of superpathogens is likely to never be counteracted by targeted therapeutic design, accelerating antibiotic resistance to greater crisis levels. In this MSCA application I aim to combine my bioengineering experience with the world-leading expertise of my host laboratory in epithelial mechanobiology to create dynamic simulations of human bladder-on-a-chip homeostasis and UTI infections. I will perform thorough analyses on the transcriptomic level of changes across the expanse of the urothelium with periodic filling and voiding during pathogenic and non-pathogenic infections. CURIES will have unparalleled relevance for the drug discovery industry. Bringing together such advanced methodologies will yield discoveries in molecular mechanisms impacted by bladder-pathogen interactions and enable computational modelling simulations to serve as predictive tools. By undertaking this work I will develop valuable transferable skills, increase my scientific visibility, and move closer to scientific independence. CURIES will both shape my academic career and positively impact the fight against antibiotic resistance.