Modelling urinary tract infections (UPEC) and bladder cancer in mice (wild type and Keap1 knockout)
Chronic inflammation is a risk factor for carcinogenesis but the underlying mechanisms remain poorly understood. Urinary tract infections (UTIs) are often recurrent or chronic sustaining repeated inflammatory insult in the urinary tract. UTIs are caused most commonly by E. coli. Urosepsis is a complication of UTIs that is potentially fatal resulting in whole-body inflammation involving multi-organ failure, particularly common in immunocompromised individuals. Sepsis causes millions of deaths globally each year, with an estimated more than 1 in 4 patient deaths. Recurrent UTIs and bacterial infections in general are becoming increasingly frequent owing to the emergence of antibiotic-resistant bacteria, which in turn may increase the economic burden of these infections on society and healthcare systems. Epidemiological studies show inconsistent results regarding bacterial UTIs as a risk factor for bladder cancer (BC). BC is the 5th most commonly diagnosed cancer and the most common urinary tract malignancy. The current ability to classify, diagnose and thereby facilitate correct management decisions is less than “optimal’’. More in-depth studies are required to understand the molecular mechanisms by which pathogens could promote carcinogenesis as well as what host factors might be important in pathogen-induced carcinogenesis. Bacillus Calmette-Guérin (BCG) is an effective adjuvant therapy for superficial bladder cancer. The anticancer effect of BCG in the treatment of bladder cancer involves a complex local immune response, including the activation of B, T and NK cells induced by multiple cytokines, e.g. interleukin (IL)-1, -6 and -8. However, only some patients benefit from this treatment. Our published and unpublished data give us reason to believe that Keap1/Rbx1/Cul3 may be important in controlling inflammation in these diseases. An in-depth understanding of the role this complex in modulating inflammatory responses in urosepsis and bladder cancers may have vital clinical implications, opening novel research venues for translational research, for instance in expanding the field of host-targeted therapy for infectious diseases and cancers. Associations of Keap1- E3 ubiquitin ligase complex with UTIs and bladder cancers could potentiate the development of new peptide-based or small molecule chemical inhibitors that could represent a new therapeutic intervention. Thus, a comprehensive study into the biology of Keap1 and related proteins continues to be warranted.
Primary goal:
To identify a cross talk between chronic UTIs and cancers, find novel mechanisms of the regulation of inflammatory signaling in urosepsis and bladder cancers and what consequences these might have for treatment outcomes.
We would require the use of specific Keap1 knockout mice in order to study the role of Keap1 in these diseases as we have not found any other alternatives to using animals. We expect to use about 384 mice throughout the entire study and will keep the use of the animals to the minimum. We believe we will make a significant contribution in identifying new mechanisms of regulating inflammation that is associated with many diseases with a potential for novel diagnostic and drug targets.
A considerable amount of distress is expected from these experiments on the mice so mice would be euthanized at the end of experiments.
Primary goal:
To identify a cross talk between chronic UTIs and cancers, find novel mechanisms of the regulation of inflammatory signaling in urosepsis and bladder cancers and what consequences these might have for treatment outcomes.
We would require the use of specific Keap1 knockout mice in order to study the role of Keap1 in these diseases as we have not found any other alternatives to using animals. We expect to use about 384 mice throughout the entire study and will keep the use of the animals to the minimum. We believe we will make a significant contribution in identifying new mechanisms of regulating inflammation that is associated with many diseases with a potential for novel diagnostic and drug targets.
A considerable amount of distress is expected from these experiments on the mice so mice would be euthanized at the end of experiments.