About Sickkids
About SickKids

Darius Jehan Bägli, MDCM, FRCSC, FAAP, FACS

The Hospital for Sick Children
Associate Head
Urology

Associate Surgeon-in-Chief
Department of Surgery

Staff Urologist
Urology

Research Institute
Senior Associate Scientist
Developmental & Stem Cell Biology

University of Toronto
Professor
Department of Surgery

Full Member
Institute for Medical Sciences

Professor
Department of Physiology


Phone: 416-813-6465 ext. 206465
Fax: 416-813-6461
e-mail: darius.bagli@sickkids.ca
Alternate Fax: Internal: 206461

For more information, visit:
Bägli Lab
Paediatric Regenerative Medicine (PRM) Program

Brief Biography

Dr. Bagli was recruited back to Canada from the United States to initiate a new direction in the evolution of the Urology Division at The Hospital for Sick Children (SickKids) and to create a basic research sphere of activity within the division. 

Dr. Bagli became a member of the surgical staff at SickKids and the Department of Surgery, University of Toronto, in 1995.  He is certified in Urologic Surgery by both the Royal College of Physicians and Surgeons of Canada, and the American Board of Urology and is a Fellow of the American Academy of Pediatrics.  

He directs a laboratory in the Developmental & Stem Cell Biology research program at SickKids Research Institute, as well as oversees a busy clinical practice in Paediatric Urology and Reconstructive Surgery.  He is currently one of a few paediatric urologists with an independent cell and molecular biology program in North America. 

Dr. Bagli is currently investigating extracurricular matrix biology as it pertains to wound healing and biomechanically-mediated injury in the lower urinary tract.  He continues to pursue innovative collaborations with clinicians and investigators at the University or Toronto in Canada and the United States.  

He has been principal author and co-author of many papers and book chapters in both clinical paediatric urology as well as basic research. 

Dr. Bagli holds peer-reviewed funding from CIHR for his research and is actively involved in both the basic science and clinical training of graduate and undergraduate students, paediatric urology fellows, and medical students.  He was recently awarded the AUA mentor award for his mentorship and research excellence, the first time such an award was given to a Canadian or paediatric urologist. 

Research Interests

The urinary bladder is the organ which stores and empties urine. From a scientific point of view, focus on the bladder has generally been in cancer or urine control problems of aging. However, a great deal remains to be learned about bladder dysfunction and disease in children. Children's bladder disorders can be quite far ranging. Our lab is studying the bladder disease which arises when the bladder is unable or unwilling to store or empty properly. This leads to tissue changes in the bladder wall which resemble overgrowth and scarring.

Previously we explored the molecular components most responsible for these changes.  Using bladder muscle cells and cultured whole bladder removed from it's host animal, as models, we tested these models using various stimuli or mechanical stretching, decreased oxygen levels and matrix alterations.  We found that ERK1/2 upregulated MMP-2 and -9 under stretch, while both mTOR and ERK increased expression of hypoxia-induced MMP7.  Indeed these two pathways appeared to coordinate SMC proliferation and fibrosis-related gene expression.  Furthermore, the undesirable changes in the bladder, such as hypertrophy and negative remodeling were targeted by mTOR inhibition.  In our recent publication, we targeted the mTOR pathway using rapamycin for prevention of specific bladder hypertrophy and remodeling.  Indeed in this article, we found that rapamycin was able to prevent hypertrophy and negative changes in remodeling of the bladder matrix (Schroeder et all, 2013).  This study has promoted us to look for other mTOR pathway inhibitors possessing even greater efficacy.  It is anticipated that our search will have useful implications for the treatment and prevention of similar bladder dysfunction in both children and later in life. 

Another translational goal that we are exploring is the reversal of already established obstruction.  Bladder obstruction causes overfilling in the bladder and sets in motion a number of signals from the surface of the cell telling it to make new proteins and grow bigger.  As discussed, inhibiting these signals during the obstructive process with the above inhibitors can prevent many aspects of the disease.  But once the bladder is already damaged, we cannot fully restore the bladder with these same inhibitors.  Even removal of the obstruction does not always restore bladder structure and function.  Bladders often remain scarred, thickened and contract poorly and/or too often.  This means that once the bladder damage has occurred, almost permanent changes have occurred in the muscle.  These changes are not genetic, since it can happen to any obstructed bladder, as we know from animal studies with normal bladders.  It appears then that it might be epigenetic, a process where the "wrapping" or structure on the DNA has been altered to cause long-term changes in how the cells acts. 

We have started to look at whether tell-tale indicators of epigenetic change are occurring, and we have found them in both petri dish models and animal studies.  We used an epigenetic microchip assay to show that there are discrete epigenetic changes occurring in smooth muscle cells cultured  under obstructed-like conditions.  Also, we found examples of epigenetic change by epigenetic array and pyrosequencing (a special method to look at epigenetic changes on the DNA) and that this correlated well with expression changes in obstructed bladders in vivo.  In our petri dish model we also found that blocking both the epigenetic and signaling processed with specific chemicals, we could restore the muscle function better than with either blocker alone.  In similar experiments, we aim to find a way to target the changes in bladder muscle function and growth by inhibiting both epigenetic and signaling processes that seem to help maintain them. 

Other studies in our lab include examination of DNA methylation markers in uropathogenic E coli infection, and also in xenoestrogen-induced alteration in the development of male genital tract. 

External Funding

  • CIHR (2009-2014). Team Grant Co-PI. Effects of brominated flame retardants on reproductive health.
  • CIHR (2009-2013). PI. Bladder smooth muscle novel molecular targets for therapy.
  • Kidney Foundation of Canada (2008-2010). PI. Bladder smooth muscle signaling.
  • Sickkids Research Institute New Ideas Grant Program: (2007). PI. Epigenetics of urinary tract infection.

Achievements

  • 1st prize Basic Science-Robson Research Day for Stat 3 Kinase in Bladder Stretch Injury (Sarel Halachmi presented). 2003
  • 2nd Prize Basic Science-Robson Research Day for Dissociated autologous urolthelial grafting for bladder augmentation in a porcine model (John Hodapp presented). 2003
  • 2nd Prize Clinical Research-Robson Research Day for The role of bacterial infection in pediatric acute epidydimo-orchitis (Sarel Halachmi presented). 2003
  • Service Award- Society for Basic Urologic Research received at the Spring 2004 annual meeting in recognition of your tremendous efforts, valuable service and insight in structuring and expanding the SBUR website and maintaining its function at a professional level. 2004

Publications