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The Contributions of Ribonuclease 4 & 7 to Urinary Tract Antibacterial Defense

Award Number: R01DK115737
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2018
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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The Contributions of Ribonuclease 4 & 7 to Urinary Tract Antibacterial Defense - PROJECT SUMMARY/ABSTRACT Urinary tract infections (UTIs), including cystitis and pyelonephritis, rank among the most prevalent bacterial infections encountered in clinical medicine. With the rising prevalence of antibiotic-resistant uropathogens, there is an urgent need for new strategies to reduce antibiotic use, prevent UTIs, and alleviate their complications. Antimicrobial peptides (AMPs), essential components of the innate immune response, offer a promising area of investigation for UTI defense. Our research team has identified Ribonuclease (RNase) 7, and more recently RNase 4, as AMPs that protect the urothelium from uropathogenic Escherichia coli (UPEC). These peptides are produced by kidney and bladder uroepithelial cells, possess robust bactericidal activity against uropathogenic bacteria and antibiotic-resistant UPEC, and exhibit minimal host toxicity. Enhancing their expression improves UPEC clearance. Conversely, reduced RNase 4 & 7 expression increases UPEC susceptibility, with lower urinary concentrations observed in children prone to UTIs. These findings form the basis of our central hypothesis that RNase 4 & 7 have indispensable roles in UTI defense. The objective of this renewal application is to address key gaps in our understanding of their antimicrobial mechanisms and regulatory control. In Aim 1, we will define how RNase 4 & 7 eliminate UPEC by identifying their bacterial targets. In doing so, we may identify potential resistance mechanisms. Aim 2 will use a multi-omics approach to define the genetic and epigenetic landscape regulating RNase 4 & 7 expression in states of health and during UTI. In Aim 3, we will evaluate whether enhancing endogenous RNase 4 & 7 expression – by repurposing clinically prescribed medications – improves UTI outcomes. Completion of these Aims will provide a comprehensive understanding of the contributions of RNase 4 & 7 to urinary tract antibacterial defenses and yield mechanistic insights into their function. Given the burden of UTIs and the growing threat of antibiotic-resistant uropathogens, foundational knowledge gained through this research could ultimately support the development of new AMP-based management approaches.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $685,156 )
2026	2026	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	6/16/2026	COMPETING CONTINUATION	$685,156
														Subtotal = $685,156

Issue Date FY: 2025 ( Subtotal = -$30,253 )
2025	2022	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/24/2025	NON-COMPETING CONTINUATION	-$30,253
														Subtotal = -$30,253

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $484,792 )
2022	2022	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/18/2022	NON-COMPETING CONTINUATION	$436,311
2022	2022	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	4/22/2022	NON-COMPETING CONTINUATION	$48,481
														Subtotal = $484,792

Issue Date FY: 2021 ( Subtotal = $484,792 )
2021	2021	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/9/2021	NON-COMPETING CONTINUATION	$484,792
														Subtotal = $484,792

Issue Date FY: 2020 ( Subtotal = $404,662 )
2020	2020	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/7/2020	NON-COMPETING CONTINUATION	$404,662
														Subtotal = $404,662

Issue Date FY: 2019 ( Subtotal = $400,698 )
2019	2019	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/20/2019	NON-COMPETING CONTINUATION	$400,698
2019	2018	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/19/2019	NEW	$0
														Subtotal = $400,698

Issue Date FY: 2018 ( Subtotal = $372,177 )
2018	2018	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/30/2018	NEW	$372,177
														Subtotal = $372,177

Grand Total All Awards = $2,802,024

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The Contributions of Ribonuclease 4 & 7 to Urinary Tract Antibacterial Defense

Award Number: R01DK115737

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2018

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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