The broad, long-term objectives of this project are to elucidate effective therapeutic interventions and biomarkers for congenital obstructive nephropathy. Congenital obstructive nephropathy is the leading cause of chronic renal failure in children, with end-stage renal failure estimated to cost 15 billion dollars annually in the United States alone. Despite surgical intervention, the standard of care for congenital urinary obstruction, the majority of patients develop chronic renal failure and about half still progress to end stage renal failure. These observations highlight the fact that a number of diagnostic, therapeutic and prognostic quandaries still exist in the management of congenital obstructive nephropathy. We have identified a novel mutant mouse line, designated mgb for megabladder, that develops overt signs of urinary tract obstruction in utero resulting in the development of hydroureteronephrosis and progressive renal failure following birth. The long-term objectives of this project are to utilize the mgb mouse model to identify effective biomarkers and therapeutic strategies for the classification and management of obstructive nephropathy early in life.
In Specific Aim 1, we propose to utilize a variety of immunohistochemical and molecular approaches to complete characterization of the pathophysiological changes observed in the kidneys of mgb mice. Recent studies in our lab indicate that a percentage of mgb mice can be rescued from imminent death by performing cutaneous vesicostomy. Based upon this observation, Specific Aim 2 will examine the efficacy of multiple therapeutic strategies designed to augment our surgical approach in mgb mice. Finally, as outlined in Specific Aim 3, the gradual progression of renal failure observed in mgb mice provides a novel platform for the identification and characterization of biomarkers that effectively predict the course of progressive kidney injury and identify individuals that are in need of more aggressive adjunctive therapeutic interventions. In summary, the mgb mouse model provides us with a novel opportunity to examine the molecular pathways associated with the development of chronic renal failure, as well as a platform for biomarker development and the assessment of surgical and therapeutic strategies designed to ameliorate the pathophysiological changes observed in these animals. Completion of the studies outlined in this proposal will help us diagnose and treat children and adults with kidney disease.

Public Health Relevance

Congenital obstructive nephropathy, kidney damage resulting from blockage of urine flow while still in the womb, is the leading cause of long-term kidney failure in children. Despite surgery to correct the blockage after birth, most children develop progressive kidney injury, leading to a poor quality of life and often early death. We have developed a mouse model that mimics congenital obstructive nephropathy. This will allow us to develop new therapies in addition to surgery and to find new markers that will tell us which children would need more than surgery alone to treat their kidneys.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
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Moxey-Mims, Marva M
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Nationwide Children's Hospital
United States
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Carpenter, Ashley R; McHugh, Kirk M (2017) Role of renal urothelium in the development and progression of kidney disease. Pediatr Nephrol 32:557-564
Li, Birong; Haridas, Babitha; Jackson, Ashley R et al. (2017) Inflammation drives renal scarring in experimental pyelonephritis. Am J Physiol Renal Physiol 312:F43-F53
Carpenter, Ashley R; Becknell, M Brian; Ching, Christina B et al. (2016) Uroplakin 1b is critical in urinary tract development and urothelial differentiation and homeostasis. Kidney Int 89:612-24
Georgas, Kylie M; Armstrong, Jane; Keast, Janet R et al. (2015) An illustrated anatomical ontology of the developing mouse lower urogenital tract. Development 142:1893-908
McHugh, Kirk M (2014) Megabladder mouse model of congenital obstructive nephropathy: genetic etiology and renal adaptation. Pediatr Nephrol 29:645-50
Becknell, Brian; Carpenter, Ashley R; Allen, Jordan L et al. (2013) Molecular basis of renal adaptation in a murine model of congenital obstructive nephropathy. PLoS One 8:e72762
Becknell, Brian; Spencer, John David; Carpenter, Ashley R et al. (2013) Expression and antimicrobial function of beta-defensin 1 in the lower urinary tract. PLoS One 8:e77714
DeSouza, Kristin R; Saha, Monalee; Carpenter, Ashley R et al. (2013) Analysis of the Sonic Hedgehog signaling pathway in normal and abnormal bladder development. PLoS One 8:e53675
Becknell, Brian; Carpenter, Ashley R; Bolon, Brad et al. (2013) Struvite urolithiasis and chronic urinary tract infection in a murine model of urinary diversion. Urology 81:943-8
Carpenter, Ashley R; Becknell, Brian; Hirselj, Daniel A et al. (2012) Urinary diversion via cutaneous vesicostomy in the megabladder mouse. Methods Mol Biol 886:393-402

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