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Contrasting roles for neutrophils and macrophages during acute pyelonephritis

Award Number: K01DK128379
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Contrasting roles for neutrophils and macrophages during acute pyelonephritis - Project Summary/Abstract Urinary tract infections (UTIs) are among the most frequent and severe infections worldwide. Uropathogenic Escherichia coli (UPEC) is the primary causative agent of UTI. UPEC ascension from the bladder (cystitis) to the kidneys results in pyelonephritis (PN). Despite prompt antibiotic treatment, patients with PN can develop acute kidney injury (AKI) and renal scarring, which can ultimately lead to end-stage renal disease. Currently, no therapy is available to prevent the long-term sequelae following PN. The innate immune system serves instrumental roles in controlling UTI and represents a potential therapeutic target for UTI prevention and treatment. However, mounting evidence argues that dysregulated innate immune responses can lead to persistent inflammation and renal scarring during PN. A greater understanding of the cellular immune mechanisms underlying the development of renal inflammation and kidney fibrosis during PN will lead to novel therapeutic strategies to treat UTI and prevent the development of detrimental sequelae. I have recently demonstrated that neutrophils and macrophages have distinct roles during PN pathogenesis. While neutrophils prevent widespread UPEC dissemination, macrophages promote pro-inflammatory and pro- fibrotic immune responses during PN. The overall objective of this proposal is to investigate the functional roles of neutrophils and macrophages in the development of kidney fibrosis and dysfunction after a PN episode. My central hypothesis is that neutrophils eradicate UPEC and prevent permanent kidney damage, while macro- phage-mediated inflammation drives kidney injury and renal scarring during PN. The specific aims during this K award will test the following hypotheses: 1) Neutrophils have a protective antimi- crobial function, while macrophages induce interstitial fibrosis and renal dysfunction during PN (Aim 1). 2) Mac- rophages exert pro-inflammatory and pro-fibrotic functions during PN, which contribute to renal inflammation, scarring, and reduced kidney function (Aim 2). 3) Neutrophil NOX2 limits bacterial dissemination during PN, whereas macrophage NOX2 promotes oxidative stress and kidney injury (Aim 3). The proposed research will use an innovative preclinical mouse model of APN that replicates the development of kidney fibrosis following UTI and bridges methodologies in the areas of immunology, microbiology, molecular biology, and nephrology. The expected outcomes from this proposal will reveal novel biological functions for macrophages and neutrophils during PN, and will identify new targets that may alleviate PN-mediated sequelae. This approach in combination with structured career development activities under the guidance of my mentors and research advisory team, will prepare me to successfully compete for R01 funding and launch my career as an independent scientist focused on resolving some of the most challenging obstacles in the treatment of UTI.


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 = $143,568 )
2025	2025	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/6/2025	NON-COMPETING CONTINUATION	$143,568
														Subtotal = $143,568

Issue Date FY: 2024 ( Subtotal = $143,568 )
2024	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/30/2024	NON-COMPETING CONTINUATION	$143,568
														Subtotal = $143,568

Issue Date FY: 2023 ( Subtotal = $143,568 )
2023	2023	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/4/2023	NON-COMPETING CONTINUATION	$143,568
														Subtotal = $143,568

Issue Date FY: 2022 ( Subtotal = $143,568 )
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	2	4/26/2022	NON-COMPETING CONTINUATION	$143,568
														Subtotal = $143,568

Issue Date FY: 2021 ( Subtotal = $145,068 )
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	1	5/19/2021	NEW	$145,068
														Subtotal = $145,068

Grand Total All Awards = $719,340

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Contrasting roles for neutrophils and macrophages during acute pyelonephritis

Award Number: K01DK128379

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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