Wednesday, April 24, 2024 4/24/2024

IMPACT OF FOREIGN BODIES ON INFECTION SUSCEPTIBILITY, DISEASE AND MUCOSAL REMODELING OF THE URINARY

Award Number: R01DK051406
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY: Urinary tract infections (UTIs) are highly prevalent (affecting over 15 million women annually in the United States), tend to recurrence and/or chronicity and are increasingly resistant to antibiotic treatment. Recent work suggests a “Lock and Key” paradigm in which UTI susceptibility is governed by complex interactions of dynamic host susceptibility determinants and diverse bacterial urovirulence potentials that are driven not only by gene content but also by differences in the expression and regulation of conserved functions. Further, catheterization of the urinary tract increases susceptibility to infection by bacteria that do not usually cause UTIs in immunocompetent people, including highly antibiotic resistant strains such as methicillin resistant Staphylococcus aureus and Klebsiella pneumoniae, a prominent member of the carbapenem resistant Enterobacteriaceae. This proposal will assess the mechanisms by which urinary catheters affect acute UTI susceptibility and long-term pathophysiology in the urinary tract (UT). Short-term urinary catheterization increases the risk of UTI and other complications up to 80%, and prolonged catheterization increases the risk to 100%. In mouse models of catheter associated UTI (CAUTI), urinary catheterization itself results in the wounding of the bladder epithelium, leading to inflammation and fibrinogen release. Fibrinogen and other host proteins are deposited on catheters in both mice and human patients. Enterococcus, a common cause of CAUTI, binds this deposited fibrinogen via the EbpA adhesin to mediate catheter adherence, biofilm formation and UT colonization, even though Enterococcus cannot directly bind the catheter. This proposal tests the hypothesis that implanted catheters increase host susceptibility to UTI by diverse potential pathogens via wounding the uroepithelium, triggering inflammation and providing novel surfaces for bacterial binding. In addition, available data suggest that inflammation and epithelial wounding due to chronic cystitis remodels the bladder mucosa, rendering it more susceptible to subsequent infection. Continual wounding due to long-term catheterization may also result in bladder mucosal remodeling and increased infection susceptibility. This proposal aims to use histological, biochemical and genetic approaches in combination with representative mouse models and human clinical samples to: i) assess the effects of catheter implantation on infection susceptibility and determine host and bacterial factors important in CAUTI; ii) investigate the host proteins and diverse bacterial adhesins that mediate binding to and biofilm formation on implanted catheters and; iii) ascertain mucosal remodeling effects of prolonged foreign body residence in the UT. Understanding the mechanisms that contribute to the increased sensitivity to infection of the UT due to catheterization will give insights into the development of more effective therapies, which are sorely needed due to the spread of multidrug resistant uropathogens.


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: 2024 ( Subtotal = $486,791 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	2/2/2024	NON-COMPETING CONTINUATION	$486,791
														Subtotal = $486,791

Issue Date FY: 2023 ( Subtotal = $543,778 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	24	2/3/2023	COMPETING CONTINUATION	$543,778
														Subtotal = $543,778

Issue Date FY: 2021 ( Subtotal = $343,125 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	23	3/15/2021	NON-COMPETING CONTINUATION	$343,125
														Subtotal = $343,125

Issue Date FY: 2020 ( Subtotal = $343,125 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	2/11/2020	NON-COMPETING CONTINUATION	$343,125
														Subtotal = $343,125

Issue Date FY: 2019 ( Subtotal = $343,125 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	2/13/2019	NON-COMPETING CONTINUATION	$343,125
														Subtotal = $343,125

Issue Date FY: 2018 ( Subtotal = $343,125 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	2/13/2018	NON-COMPETING CONTINUATION	$308,812
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	20	4/26/2018	NON-COMPETING CONTINUATION	$34,313
														Subtotal = $343,125

Issue Date FY: 2017 ( Subtotal = $343,125 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	19	5/15/2017	COMPETING CONTINUATION	$54,628
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	19	1/28/2017	COMPETING CONTINUATION	$343,125
2017	2015	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	18	5/8/2017	NON-COMPETING CONTINUATION	-$54,628
2017	2015	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	1/24/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $343,125

Issue Date FY: 2015 ( Subtotal = $330,600 )
2015	2015	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	6/29/2015	NON-COMPETING CONTINUATION	$330,600
														Subtotal = $330,600

Issue Date FY: 2014 ( Subtotal = $330,600 )
2014	2014	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	7/15/2014	NON-COMPETING CONTINUATION	$330,600
														Subtotal = $330,600

Issue Date FY: 2013 ( Subtotal = $319,030 )
2013	2013	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	7/11/2013	NON-COMPETING CONTINUATION	$319,030
														Subtotal = $319,030

Issue Date FY: 2012 ( Subtotal = $330,600 )
2012	2012	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	15	8/23/2012	COMPETING CONTINUATION	$330,600
2012	2011	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	8/21/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $330,600

Issue Date FY: 2011 ( Subtotal = $316,572 )
2011	2011	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	12/22/2010	NON-COMPETING CONTINUATION	$287,792
2011	2011	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	14	5/26/2011	NON-COMPETING CONTINUATION	$28,780
														Subtotal = $316,572

Issue Date FY: 2010 ( Subtotal = $419,769 )
2010	2010	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	13	1/27/2010	NON-COMPETING CONTINUATION	$319,770
2010	2010	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Trans-NIH Recovery Act Research Support	000	12	12/7/2009	SUPPLEMENT FOR EXPANSION	$99,999
														Subtotal = $419,769

Issue Date FY: 2009 ( Subtotal = $323,000 )
2009	2009	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	2/2/2009	NON-COMPETING CONTINUATION	$290,700
2009	2009	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	12	3/2/2009	NON-COMPETING CONTINUATION	$32,300
														Subtotal = $323,000

Issue Date FY: 2008 ( Subtotal = $323,000 )
2008	2008	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Kidney Diseases, Urology and Hematology Research	000	11	3/10/2008	COMPETING CONTINUATION	$323,000
														Subtotal = $323,000

Issue Date FY: 2006 ( Subtotal = $351,101 )
2006	2006	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Kidney Diseases, Urology and Hematology Research	000	10	1/17/2006	NON-COMPETING CONTINUATION	$351,101
														Subtotal = $351,101

Issue Date FY: 2005 ( Subtotal = $359,550 )
2005	2005	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Kidney Diseases, Urology and Hematology Research	000	9	12/20/2004	NON-COMPETING CONTINUATION	$359,550
														Subtotal = $359,550

Issue Date FY: 2004 ( Subtotal = $359,550 )
2004	2004	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Kidney Diseases, Urology and Hematology Research	000	8	11/20/2003	NON-COMPETING CONTINUATION	$359,550
														Subtotal = $359,550

Issue Date FY: 2003 ( Subtotal = $359,550 )
2003	2003	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Kidney Diseases, Urology and Hematology Research	000	7		NON-COMPETING CONTINUATION	$359,550
														Subtotal = $359,550

Issue Date FY: 2002 ( Subtotal = $360,725 )
2002	2002	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Kidney Diseases, Urology and Hematology Research	000	6	1/29/2002	COMPETING CONTINUATION	$360,725
														Subtotal = $360,725

Issue Date FY: 2001 ( Subtotal = $234,479 )
2001	2001	WASHINGTON UNIVERSITY	7425 FORSYTH	CLAYTON	MO	63105	SAINT LOUIS	USA	Kidney Diseases, Urology and Hematology Research	000	5	1/11/2001	NON-COMPETING CONTINUATION	$234,479
														Subtotal = $234,479

Grand Total All Awards = $8,127,579

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IMPACT OF FOREIGN BODIES ON INFECTION SUSCEPTIBILITY, DISEASE AND MUCOSAL REMODELING OF THE URINARY

Award Number: R01DK051406

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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