Research Objectives
The goals of pediatric urology basic research within Duke’s Department of Urology include:
- To understand how bladder outlet obstruction—which affects children with posterior urethral valves, spina bifida, and other congenital issues—damages the bladder and leads to urinary incontinence and renal failure.
- To develop a treatment strategy for diabetic patients who suffer from urinary problems such as frequency, urgency, and incontinence.
Research Approach
The Duke University Urinary Dysfunction Laboratory is led by J Todd Purves MD, PhD, principal investigator, and Francis “Monty” Hughes Jr., lab director, and is located in the Medical Sciences Research Building. The focus of the laboratory is on how the innate immune system responds to problems such as outlet obstruction or diabetes and how to manipulate the immune system to prevent bladder damage. We have found that the NLRP3 inflammasome, located in the urothelium (the inside lining of the bladder) is responsible for sensing stressful events and then initiating an inflammatory process. Using NLRP3 as a target for new medicinal therapy, we have found that inhibitors to this pattern recognition receptor prevents scarring of the bladder and injury to the nerves that are necessary for good urinary function.
Basic Research Initiatives
Bladder outlet obstruction affects children who have anatomic blockage of their lower urinary tract, for example, posterior urethral valves and urethral stricture, as well as children who have physiological obstruction, such as those with spina bifida or other neurological problems. We have been conducting an NIH funded project that studies this problem in a rat model. Our results have shown that high bladder pressures, which occur as the bladder tries to push past the obstruction, triggers the activation of the NLRP3 inflammasome located in the cells lining the bladder (urothelium). Activation of the inflammasome leads to a chronic state of inflammation that causes scarring and loss of the nerves that are important for proper function. We have found that preventing activation of the inflammasome with pharmaceutical inhibitors prevents inflammation and scarring while protecting the nerves in the setting of bladder outlet. In the future, we will be testing new compounds that we hope will improve and preserve bladder function in our young patients who suffer from these chronic conditions.
Diabetes is a common metabolic illness that is increasingly more common in children. While it is well known that diabetic patients encounter more problems with urinary function, including an increased risk for urinary tract infections, urinary frequency, urgency, and incontinence, there are currently no specific treatments available for these patients. We have begun clinical monitoring of diabetic patients and found that there is a very high incidence of urinary problems even in children who were only recently diagnosed with this disease. As this is a chronic problem that typically worsens with time, it is important to understand exactly how this problem occurs. In the laboratory, we have developed mouse models to study this condition and we have shown that the metabolic dysregulation of diabetes causes inflammation of the bladder which can be prevented with a novel class of inhibitors. While this project is still in an early phase, our hope is to create a treatment so that we can prevent bladder problems that too frequently develop in our young diabetic patients.
Contact Information
J Todd Purves MD PhD
Associate Professor of Surgery
Duke University Medical Center
Box 3831
Durham NC 27710
E-mail: todd.purves@duke.edu
Phone: 919-684-6994
Jonathan Routh, MD, MPH
Associate Professor of Surgery
Associate Professor in Pediatrics
Duke University Medical Center
Box 3831
Durham NC 27710
E-mail: jonathan.routh@duke.edu
Phone: 919-684-6994
John Wiener, MD
Professor of Surgery
Associate Professor in Pediatrics
Duke University Medical Center
Box 3831
Durham NC 27710
E-mail: john.wiener@duke.edu
Phone: 919-684-6994