Molecular mechanisms of distension and hypoxia induced damage of the bladder muscle during outlet obstruction, and options for pharmacologigal prevention and therapy by intervention on a molecular level

• Applicant: Privatdozentin Dr. Annette Schröder
• Subject Area: Reproductive Medicine, Urology ; Pediatric and Adolescent Medicine
• Term: from 2011 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 202566421

Urinary bladder obstruction leads to myocyte hypertrophy, hyperplasia and extracellular matrix (ECM) deposition. Ensuing bladder dysfunction causes incontinence, recurrent urinary infection, and chronic kidney damage. For 40 years, anticholinergic drugs still remain the sole medical therapy for bladder muscle dysfunction, treating only bladder symptoms, with many side effects.Overall research goals are to identify the underlying molecular mechanisms of maladaptive bladder tissue responses due to obstruction, and define drug therapies to correct or prevent these responses. Obstruction creates a primary pressure/distension injury. The bladder muscle also becomes hypoxic, likely from microvascular compression during excessive distension. However, during obstruction in vivo, hypoxia never occurs without the distension stimulus. Therefore, we hypothesize that bladder responses to the primary distension stimulus are modulated by hypoxia, and are amenable to specific therapy tailored to impact signaling pathways shared by these two stimuli. To address this hypothesis, the group developed an ex vivo rat bladder organ culture system that permits selective recombination of the distension and hypoxia stimuli, an approach not possible in vivo. Our objective is to integrate a whole organ, cell culture, and therapeutic in vivo approach to reveal novel mechanisms and treatment for bladder obstruction. Specific Aims are 1. to elucidate the signaling effectors of mTOR that mediate hypoxic modulation of distension responses in vitro (mTOR, the mammalian Target of Rapamycin, is a kinase that regulates cell growth, cell proliferation, cell motility and cell survival) and 2. to evaluate mTOR & EGFR inhibitor therapy of bladder decompensation during obstruction in vivo. (The EGFR (Epidermal-Growth-Factor-Receptor) is a transmembrane receptor-tyrosine-kinase, activating the Akt-signaling pathway as receptor for growth-factors, and thereby indirectly activating mTOR ).

• DFG Programme: Research Fellowships
• International Connection: Canada
• Host: Professor Dr. Darius Bägli