The candidate's long-term goal is to become an accomplished independent physician-scientist in academic pediatric nephrology with clinical and research expertise in the diagnosis, treatment, and prevention of urinary tract infections (UTI). This mentored K08 Career Development Award proposal outlines a plan where the candidate will train under the guidance of a team of mentors and collaborators that have a successful track record of working together. This Research Advisory Team has extensive experience and success in guiding trainees and junior faculty to successful careers as independent physician-scientists. The candidate will benefit from state-of-the-art facilities and extensive support from clinical, basic, and general core services. He will acquire new research and analytical skills from hands-on directed laboratory mentorship and a classroom- based education at The Ohio State University. He 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 proposed research project are to improve the care of pediatric patients with UTIs by identifying effective early biomarkers and novel treatment options for the diagnosis and treatment of UTIs. The proposed research project will test the hypothesis that antimicrobial peptides (AMP), a ubiquitous component of the innate immune system, are important in the regulation and prevention of UTIs. The proposed research will define the function of a novel AMP, ribonuclease 7 (RNase 7), which has recently been shown to have potent antimicrobial properties and play an important role in maintaining urinary tract sterility. The anticipated outcome of this work is advancement of our understanding of the role of RNase 7 in the prevention and treatment of UTIs and to identify the potential use of this protein in UTI diagnostics and therapeutics.
Specific Aim 1 is designed to characterize the antimicrobial properties of RNase 7 in states of health and infection.
Specific Aim 2 is designed to characterize RNase 7 at the structural and functional level by identifying critical amino acid residues that are responsible for its antimicrobial function.
Specific Aim 3 is designed to evaluate the frequency and biological relevance of single nucleotide polymorphisms in RNASE7. Successful completion of these proposed aims and educational plan will help develop the needed expertise to systematically evaluate AMPs, like RNase 7, in the human urinary tract.
Urinary tract infections are one of the most common and serious bacterial infections encountered by physicians. No treatment strategy has proven to be effective in the prevention of UTI sequelae, and antibiotic resistance is increasing in uropathogenic bacteria. Antimicrobial peptides (AMP), a component of the innate immune system, are a promising new class of potential antibiotics that may overcome the limitations of traditional therapies and the emerging problems of bacterial resistance. In this study, we will evaluate the structure, function, and biological relevance of ribonuclease 7, a novel AMP that has potent antimicrobial properties in the human urinary tract.
|Schwaderer, Andrew L; Wang, Huanyu; Kim, SungHwan et al. (2016) Polymorphisms in Î±-Defensin-Encoding DEFA1A3 Associate with Urinary Tract Infection Risk in Children with Vesicoureteral Reflux. J Am Soc Nephrol 27:3175-3186|
|Watson, Joshua R; Hains, David S; Cohen, Daniel M et al. (2016) Evaluation of novel urinary tract infection biomarkers in children. Pediatr Res 79:934-9|
|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|
|Becknell, Brian; Eichler, Tad E; Beceiro, Susana et al. (2015) Ribonucleases 6 and 7 have antimicrobial function in the human and murine urinary tract. Kidney Int 87:151-61|
|Becknell, Brian; Schwaderer, Andrew; Hains, David S et al. (2015) Amplifying renal immunity: the role of antimicrobial peptides in pyelonephritis. Nat Rev Nephrol 11:642-55|
|Korbel, Lindsey; Spencer, John David (2015) Diabetes mellitus and infection: an evaluation of hospital utilization and management costs in the United States. J Diabetes Complications 29:192-5|
|Spencer, John David; Jackson, Ashley R; Li, Birong et al. (2015) Expression and Significance of the HIP/PAP and RegIIIÎ³ Antimicrobial Peptides during Mammalian Urinary Tract Infection. PLoS One 10:e0144024|
|Becknell, Brian; Schober, Megan; Korbel, Lindsey et al. (2015) The diagnosis, evaluation and treatment of acute and recurrent pediatric urinary tract infections. Expert Rev Anti Infect Ther 13:81-90|
|Spencer, John David; Schwaderer, Andrew L; Becknell, Brian et al. (2014) The innate immune response during urinary tract infection and pyelonephritis. Pediatr Nephrol 29:1139-49|
|Spencer, John D; Schwaderer, Andrew L; Eichler, Tad et al. (2014) An endogenous ribonuclease inhibitor regulates the antimicrobial activity of ribonuclease 7 in the human urinary tract. Kidney Int 85:1179-91|
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