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Chromogranin A as a Regulator of Urothelial Antimicrobial Responses During Urinary Tract Infection

Award Number: R21AI142528
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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#7. PROJECT SUMMARY A major gap exists in our understanding of how neuroendocrine mediators impact urothelial innate immune regulation to increase the risk for urinary tract infection (UTI) in females. During UTI, epithelial Toll-like Receptors (TLRs) detect microbial components to induce antimicrobial peptides (AMPs), innate immune factors that exhibit direct microbicidal activity and stimulate subsequent immune responses. We previously determined that psychological stress and the loss of the neuroendocrine protein, chromogranin A (CHGA), increased the susceptibility to skin infection by decreasing AMP responses. Our objective is to expand this area of urinary clinical research by identifying a role for psychological stress and CHGA in modulating urothelial AMP responses. Our long-term goal is to identify the mechanisms by which CHGA modulates TLR- dependent urothelial AMP responses, and relate these changes to UTI risk in humans. The objective here is to characterize CHGA-mediated AMP dysfunction in human urothelial cells and in a mouse model of Escherichia coli (UPEC) infection. Our hypothesis is that aberrant production of CHGA/Cst contributes to UPEC susceptibility by compromising inherent urothelial AMP responses. Our hypothesis was formulated based on observations from our lab that the loss of CHGA increases the susceptibility to skin bacterial infection in mice, and that catestatin, a CHGA-derived peptide released in response to stress, modulates epithelial AMP responses. Our rationale is that no one has investigated the role of CHGA in TLR-dependent urothelial AMP responses in the context of UTI, even though activation of the neuroendocrine system is impaired in several disorders of the female urinary tract. Driven by compelling published data in skin and pilot data in urothelial cells, our hypothesis will be evaluated by addressing two Specific Aims: 1.) We will use pharmacologic approaches to assess the effect of CHGA and catestatin peptides (wild-type and mutant) on AMP production and activity in primary human urothelial cells (HUCs) and urothelial organotypic rafts 2.) We will determine the role of CHGA in the urothelial AMP response to UPEC infection in vivo using mice deficient in urothelial CHGA. Our approach is innovative by using high-throughput molecular and proteomic approaches and tissue-specific knock-out mice to establish a role for CHGA in modulating urothelial AMP responses during UPEC infection. The proposed research is significant, because it will begin to dissect the mechanisms of urothelial AMP dysregulation caused by CHGA deficiency, in a controlled setting, using novel human urothelial cell and genetic mouse models in parallel, which will provide the foundation for future R01 applications and human clinical trial networks focused on UTIs. Our study results are anticipated to greatly improve our knowledge of urothelial AMP regulation by CHGA, which may lead to novel strategies to manipulate CHGA-mediated AMP responses to ameliorate the frequency or severity of UTIs in females.


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: 2023 ( Subtotal = $0 )
2023	2020	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Allergy and Infectious Diseases Research	000	2	11/23/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = -$158,562 )
2022	2020	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Allergy and Infectious Diseases Research	000	2	4/13/2022	NON-COMPETING CONTINUATION	-$158,562
														Subtotal = -$158,562

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	LOYOLA UNIVERSITY OF CHICAGO	2160 S FIRST AVE	MAYWOOD	IL	60153	COOK	USA	Allergy and Infectious Diseases Research	000	2	8/31/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $190,625 )
2020	2020	LOYOLA UNIVERSITY OF CHICAGO	2160 S FIRST AVE	MAYWOOD	IL	60153	COOK	USA	Allergy and Infectious Diseases Research	000	2	1/17/2020	NON-COMPETING CONTINUATION	$190,625
														Subtotal = $190,625

Issue Date FY: 2019 ( Subtotal = $228,438 )
2019	2019	LOYOLA UNIVERSITY OF CHICAGO	2160 S FIRST AVE	MAYWOOD	IL	60153	COOK	USA	Allergy and Infectious Diseases Research	000	1	1/31/2019	NEW	$228,438
														Subtotal = $228,438

Grand Total All Awards = $260,501

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Chromogranin A as a Regulator of Urothelial Antimicrobial Responses During Urinary Tract Infection

Award Number: R21AI142528

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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