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The Contribution of Ribonuclease 7 to Urinary Tract Anitbacterial 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: 01/31/2025

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The Contribution of Ribonuclease 7 to Urinary Tract Anitbacterial Defense - ABSTRACT Urinary tract infections (UTIs), including pyelonephritis, are among the most common and serious infections encountered in clinical practice. No proven treatment options exist to prevent UTI. New strategies are needed to augment the ability of host defenses to prevent UTI and minimize UTI-associated morbidity. A growing body of evidence, from our laboratory and others suggests that antimicrobial peptides (AMP), an essential component of the innate immune response, protect the urinary tract from invasive bacterial infection. Our research team has identified Ribonuclease 7 (RNase 7) as a potent and highly abundant human AMP that shields the urothelium from uropathogenic E. coli (UPEC). Our published data suggest that RNase 7 is an ideal AMP to develop as a UTI therapeutic because: (A) it has potent antibacterial activity; (B) it is highly abundant in the urinary tract; (C) it is produced by cell types that are targeted by UPEC; and (D) it has minimal toxicity. Our emerging data suggest that RNase 7 induction shields the urothelium from UPEC, while suppressed RNase 7 production renders it susceptible to pathogens. Together, these findings provide strong support to our central hypothesis that RNase 7 is biologically necessary to maintain urine sterility and prevent UTI. Our current understanding of RNase 7's effects on innate defenses is limited in vivo because its expression is absent in the laboratory mouse and restricted to higher order vertebrates and humans. To fill this key knowledge gap, we developed two novel humanized RNase 7 mouse models. These models will be used to complete our overall objective of this application, which is to further investigate the essential contributions of RNase 7 to urine sterility. To test our central hypothesis, we will evaluate how cell-specific RNase 7 expression impacts UTI risk in vivo using a novel Rosa26 knock-in mouse (Aim 1). In Aim 2, we will investigate the molecular mechanisms that regulate RNase 7 expression using a novel humanized transgenic mouse that expresses RNase 7 under the control of its own promoter. In Aim 3, we will evaluate how human genetic polymorphisms affect RNase 7 expression and antimicrobial activity. Completion of the proposed Aims will further define the necessary contributions of RNase 7 to urine sterility and may provide the foundation to develop RNase 7 as a novel therapeutic that improves UTI outcomes. Given the clinical impact of UTI, in an era of emerging antibiotic resistant uropathogens, identifying mechanisms to develop RNase 7 as a new UTI therapy may have significant benefits to public health.


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: 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 = $2,116,868

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The Contribution of Ribonuclease 7 to Urinary Tract Anitbacterial 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: 01/31/2025

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