Relevant Degree Programs
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Nov 2019)
Urinary tract obstruction is a major cause of morbidity and mortality worldwide. Obstruction occurs in both the fetus and adult, can lead to impaired renal development, substantial renal injury, dysplasia, or progressive fibrosis of the kidney. Though different in outcome, fetal and adult obstruction both impair normal kidney function and promote the onset of chronic kidney disease. While a substantial amount of research has identified key features in the pathogenesis of obstruction, our understanding of the early events in the progression of obstructive injury is incomplete.In this thesis, I have used several experimental models to investigate the role of medullary and collecting duct injury following urinary tract obstruction. Research using these models has provided many key findings. First, I have established the previously unreported ontogeny of the collecting duct in the human fetal kidney. Second, I have defined the impact of urinary tract obstruction on the collecting duct and linked it to collecting duct injury. Third, I have characterized the response of the collecting duct and associated renal interstitium to obstruction, and identified cellular dedifferentiation and phenotypic transition as common outcomes of collecting duct injury. Last, I have characterized the expression, localization and protein-complex formation of TRPV4, and highlighted a mechanism for TRPV4 in the transduction of physical injury into a collecting duct epithelial response.Through investigation of clinical cases of fetal urinary tract obstruction and experimentation using 2 models of fetal and adult obstruction, I have demonstrated that collecting duct epithelial injury and remodeling is a common and conserved feature of obstructive injury and I have described a role for TRPV4 in the mechanosensation and transduction of the physical stimuli caused by obstructive injury. I believe TRPV4-mediated signal transduction, in part, provides a unifying mechanism for the induction of a repair and fibrosis during both fetal and postnatal urinary tract obstruction.
Master's Student Supervision (2010 - 2018)
Renal dysplasia associated with congenital urinary tract obstruction remains the major cause of end-stage renal disease in young children. The outcomes of the most severely affected boys with posterior urethral valves have not changed since the introduction of fetal intervention over twenty years ago. Poor outcomes likely reflect our limited understanding of the pathophysiology of congenital obstructive nephropathy. The first part of this thesis summarizes the challenges of diagnosis and management of this condition that are based on the assessment of fetal tubular function rather than on tests reflecting the degree of dysplastic changes. The importance of the new biomarker development based on proteomic techniques is also presented. One of the processes leading to renal dysplasia, epithelial-mesenchymal transition (EMT), is presented for the first time in human fetal kidneys in the initial study of this thesis. Characteristic changes of EMT in the collecting duct epithelium consist of the decreased expression of epithelial proteins, increased expression of mesenchymal proteins, disruption of the basement membrane, and deposition of extracellular matrix into the surrounding interstitium. Molecular and cellular signaling events of the phenotypic epithelial transition are presented in the subsequent study in which a modulatory role of Y-box binding protein-1 (YB-1) on EMT is described. Inactivation of YB-1 leads to attenuation of EMT, a fact that might have therapeutic implications and deserves further exploration. Cellular signaling pathways of EMT are also described in this study. The final project of this thesis describes clinical utility of the identified candidate proteins as urinary biomarkers of congenital obstructive nephropathy in patients with posterior urethral valves (PUV). The differential expression of proteins involved in EMT, renal fibrosis, and sensing of urine flow in patients with PUV and controls is presented, as well as their correlation to the degree of renal impairment. The results presented in this thesis contribute to our understanding of the pathophysiology of congenital obstructive nephropathy, and identify key proteins involved in this process that could be measured in urine and used as biomarkers of this devastating disease.