The candidate's long-term goal is to become an accomplished clinician-scientist in the field of pediatric nephrology with clinical and research expertise in the diagnosis, prognosis and management of congenital obstructive nephropathy. This mentored career development award proposal outlines a plan that will ultimately lead to the candidate becoming a successful independent investigator in academic pediatric nephrology. The candidate will pursue a career development plan that focuses on the continuous application of new skills in a mentored research experience. She will perform research under the mentorship of a skilled researcher with extensive experience and success in guiding trainees and junior faculty to successful careers as independent scientists. She will benefit from state-of-the-art facilities and extensive support from basic, clinical and general core services. She will acquire new research and analytical skills and enhance existing abilities. She will build a repertoire of competencies in oral and written scientific communication;academic team leadership and collaboration;and grantsmanship. The long-term objectives of the research project are to improve the care of pediatric patients with congenital obstructive nephropathy by identifying effective early biomarkers for the diagnosis and prognosis of congenital obstructive nephropathy, as well as elucidating novel therapeutic targets for this devastating condition. The proposed research will test the hypothesis that microRNAs (miRNAs) play important roles in the renal response to congenital urinary obstruction, and that miRNAs therefore represent a novel class of potential biomarkers and therapeutic targets in congenital obstructive nephropathy. For these studies, we propose to use the megabladder (mgb) mouse, a unique genetic model that develops chronic and end-stage kidney disease secondary to a functional lower urinary tract obstruction, as a model system for the discovery of potential biomarkers and the testing of novel therapies. The anticipated outcome of this work is advancement of our understanding of the role miRNAs play in congenital obstructive nephropathy and the potential of this important class of regulators in biomarker discovery and therapeutics.
Specific Aim 1 is designed to broaden our preliminary characterization of miRNA expression in the mgb mouse model to a range of time points and disease severities, including examination of the effects of a therapeutic intervention (cutaneous vesicostomy) on miRNA expression.
Specific Aim 2 is a translational study, taking the animal results back to the bedside to explore expression of specific miRNAs in patient samples, and lay the groundwork for further development of miRNAs in urinary exosomes as biomarkers of chronic kidney disease.
Specific Aim 3 explores the potential of miRNA-targeted therapeutics in the mgb mouse model of congenital obstructive nephropathy.
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 urine blockages after birth, many children with this problem develop progressive kidney injury, leading to a poor quality of life and often early death. In this study, we use a new mouse model that mimics congenital obstructive nephropathy to identify markers that can reveal early signs of kidney injury. We will examine patient urine samples for changes in these markers, and also test whether therapies aimed at these molecules can change the course of the disease in the animal model.
|Eichler, Tad E; Becknell, Brian; Easterling, Robert S et al. (2016) Insulin and the phosphatidylinositol 3-kinase signaling pathway regulate Ribonuclease 7 expression in the human urinary tract. Kidney Int 90:568-79|
|Wilhide, Michael E; Feller, James D; Li, Birong et al. (2016) Renal epithelial miR-205 expression correlates with disease severity in a mouse model of congenital obstructive nephropathy. Pediatr Res 80:602-9|
|Becknell, Brian; Mohamed, Ahmad Z; Li, Birong et al. (2015) Urine Stasis Predisposes to Urinary Tract Infection by an Opportunistic Uropathogen in the Megabladder (Mgb) Mouse. PLoS One 10:e0139077|
|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|