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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK085242-04
Application #
8420537
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Moxey-Mims, Marva M
Project Start
2010-03-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$292,163
Indirect Cost
$47,887
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
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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
Carpenter, Ashley; Paulus, Andrew; Robinson, Melissa et al. (2012) 3-Dimensional morphometric analysis of murine bladder development and dysmorphogenesis. Dev Dyn 241:522-33
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