My long-term career objective is to become an independently funded, accomplished physician-scientist with clinical and research expertise in the prevention of pyelonephritis and its sequelae in children. As a pediatric nephrologist, I aim t leverage clinical and scientific training to prevent deterioration of kidney function in these patients. To accomplish these objectives, this K08 Mentored Clinical Scientist Development Award proposal outlines a plan to facilitate the acquisition of key research and career advancement skills under the mentorship of Dr. Kirk McHugh. Additional expertise will be provided by Drs. David Hains and Sheryl Justice, two investigators with whom I already have an established record of scientific collaboration and productivity. Together, this Research Advisory Committee will provide guidance to successfully transition from a junior investigator to an independently funded physician-scientist. I will benefit further from state-of-the-art facilities ad core services located at Nationwide Children's Hospital and The Ohio State University. During my training, I will acquire new experimental and analytical skills in the laboratory as well as through classroom- based education at The Ohio State University. I will develop skills in oral and written presentation of research, scientific collaboration, leadership of a research team, and grantsmanship. The long-term research objectives of this work are to elucidate the pathogenic mechanisms of pyelonephritis and its sequelae in children, and to devise improved diagnostic, prognostic and therapeutic approaches to their care. My short-term career goal is to define the pathogenesis of pyelonephritis in children with congenital obstructive nephropathy (CON). Children with CON are especially vulnerable to pyelonephritis, which is an independent risk factor for prolonged hospitalization and progression to end-stage renal disease in this patient population.[1-3] I have identified significant changes in gene expression, morphology, and composition of renal urothelium in a murine model of CON. I hypothesize that CON perturbs structural and functional properties of renal urothelium, placing patients at risk for pyelonephrits and renal scarring.
In Specific Aim 1, I will define the relationship between hydronephrosis and structural integrity of renal urothelium.
In Specific Aim 2, I will investigate the consequences of CON on bacterial binding and the expression of infection susceptibility genes by renal urothelium.
In Specific Aim 3, I will determine if CON increases host susceptibility to experimental pyelonephritis and renal scarring. Completion of these research aims and the training proposed in my educational plan will allow me to develop the foundation to successfully compete for independent R01 funding in the future.
Congenital obstructive nephropathy (CON) is the leading cause of chronic kidney disease in children, yet few therapeutic strategies exist to prevent progressive loss of kidney function in this patient population. Obstruction is considered a clinica risk factor for pyelonephritis, which leads to renal scarring and further loss of kidney function. Recurrent pyelonephritis following surgical relief of obstruction argues against the theory that pyelonephritis arises entirely as a consequence of urine stasis. In this application, we will test the hypothesis that CON results in altered structural and functional properties of renal urothelium, thereby placing patients at risk for pyelonephritis and renal scarring. Completion of the proposed aims will generate fundamental insights regarding the pathogenesis of pyelonephritis and establish the foundation for new treatment paradigms to prevent pyelonephritis and loss of kidney function in children with CON.
|Jackson, Ashley R; Li, Birong; Cohen, Shira H et al. (2018) The uroplakin plaque promotes renal structural integrity during congenital and acquired urinary tract obstruction. Am J Physiol Renal Physiol 315:F1019-F1031|
|Ching, Christina B; Gupta, Sudipti; Li, Birong et al. (2018) Interleukin-6/Stat3 signaling has an essential role in the host antimicrobial response to urinary tract infection. Kidney Int 93:1320-1329|
|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|
|Schwaderer, Andrew L; Wang, Huanyu; Kim, SungHwan et al. (2016) Polymorphisms in ?-Defensin-Encoding DEFA1A3 Associate with Urinary Tract Infection Risk in Children with Vesicoureteral Reflux. J Am Soc Nephrol 27:3175-3186|
|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; Spencer, John David (2016) A Review of Ribonuclease 7's Structure, Regulation, and Contributions to Host Defense. Int J Mol Sci 17:423|
|Gordon, Zachary N; McLeod, Daryl J; Ching, Christina B et al. (2016) Uroepithelial thickening improves detection of vesicoureteral reflux in infants with prenatal hydronephrosis. J Pediatr Urol 12:257.e1-7|
|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|
|Spencer, John David; Jackson, Ashley R; Li, Birong et al. (2015) Expression and Significance of the HIP/PAP and RegIII? Antimicrobial Peptides during Mammalian Urinary Tract Infection. PLoS One 10:e0144024|
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