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Long-term effects of acute renal failure

Award Number: R01DK063114
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: 07/01/2003
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Long-term effects of acute renal failure - Acute kidney injury (AKI) is a significant factor predisposing chronic kidney disease (CKD), however the factors mediating CKD progression are not clear. T-helper 17 cells (Th17) represent a primary lymphocyte population and may play a central role in coordinating immune and renal cell activity in AKI and subsequent CKD induced by exposure to high salt diet. Studies from the recent project period demonstrated that impairment of IL17 activity attenuates both AKI and progression of CKD and hypertension. We also demonstrated the dependence of Th17 activity on the store-operated calcium channel, Orai1. However, there remains important questions regarding Th17 effects on AKI and CKD. First, the phenotype Th17 cells at different stages of AKI or CKD is not known; second, the physiological regulatory factors modulate Th17 reactivation associated with CKD are not defined; third, the effect of Th17 activity on the variety of potential renal cell targets is incompletely defined. We hypothesize that the dynamic regulation of Th17 cells plays a central role in the development of kidney injury, repair and progression to chronic kidney disease. We propose that Ca2+ signaling stimulated by high-salt diet increases the pathogenicity of Th17 cells by changing their cytokine profile, and further propose that the pleiotropic activity Th17 cytokines such as IL17A and GM-CSF alters parenchymal, innate, and adaptive immune cell function to promote kidney injury. Aim 1 of the proposal will utilize IL17A reporter mice to more completely define the phenotype and localization of Th17 cells using FACS, imaging tissue cytometry and evaluate spatial distribution of Th17 with developing tertiary lymphoid structures (TLS). A Th17 fate- tracing model will be used to characterize whether quiescent Th17 cells following recovery from AKI, express the Orai1- Ca2+ channel, contribute T-memory populations, differentiate to other T-helper populations, or are essential for the reactivation of Th17 cells during progression of CKD. Finally, we will determine if inhibition of these pathways using an FDA approved SOCC blocker following the establishment of AKI during the recovery phase, impairs the secondary activation of Th17 cells associated with progression of CKD. In aim 2, we will expand studies to define alterations in the transcriptional signature of Th17 cells during progressive CKD induced by high salt diet. In addition, we will determine how inhibition of the Th17 pathway by pharmacological and gene knockout approaches affects immune and renal cell transcriptional responses to injury and investigate specific alterations in B-cells and formation of TLS. Finally, we will examine the potential contribution of GM-CSF, a factor co-secreted byTh17 cells, during AK and the AKI to CKD transition.


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 = $524,862 )
2026	2026	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	3/2/2026	NON-COMPETING CONTINUATION	$524,862
														Subtotal = $524,862

Issue Date FY: 2025 ( Subtotal = $524,862 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	20	8/20/2025	NON-COMPETING CONTINUATION	$0
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	20	7/8/2025	NON-COMPETING CONTINUATION	$524,862
2025	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	3/31/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $524,862

Issue Date FY: 2024 ( Subtotal = $545,742 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	19	5/20/2024	COMPETING CONTINUATION	$545,742
2024	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	5/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $545,742

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	8/8/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $489,836 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	7/13/2021	NON-COMPETING CONTINUATION	$489,836
														Subtotal = $489,836

Issue Date FY: 2020 ( Subtotal = $489,836 )
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	7/16/2020	NON-COMPETING CONTINUATION	$489,836
														Subtotal = $489,836

Issue Date FY: 2019 ( Subtotal = $489,836 )
2019	2019	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	7/11/2019	NON-COMPETING CONTINUATION	$489,836
														Subtotal = $489,836

Issue Date FY: 2018 ( Subtotal = $494,089 )
2018	2018	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	15	7/19/2018	NON-COMPETING CONTINUATION	$494,089
2018	2016	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	1/16/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $494,089

Issue Date FY: 2017 ( Subtotal = $516,769 )
2017	2017	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	14	9/19/2017	COMPETING CONTINUATION	$516,769
2017	2016	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	9/18/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $516,769

Issue Date FY: 2016 ( Subtotal = $339,300 )
2016	2016	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	2/3/2016	EXTENSION WITH OR WITHOUT FUNDS	$339,300
														Subtotal = $339,300

Issue Date FY: 2015 ( Subtotal = $339,300 )
2015	2015	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	2/11/2015	NON-COMPETING CONTINUATION	$339,300
														Subtotal = $339,300

Issue Date FY: 2014 ( Subtotal = $339,300 )
2014	2014	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	11	2/21/2014	NON-COMPETING CONTINUATION	$33,930
2014	2014	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	1/14/2014	NON-COMPETING CONTINUATION	$305,370
														Subtotal = $339,300

Issue Date FY: 2013 ( Subtotal = $339,300 )
2013	2013	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	3/14/2013	COMPETING CONTINUATION	$339,300
														Subtotal = $339,300

Issue Date FY: 2011 ( Subtotal = $353,912 )
2011	2011	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	6/23/2011	NON-COMPETING CONTINUATION	$353,912
														Subtotal = $353,912

Issue Date FY: 2010 ( Subtotal = $363,079 )
2010	2010	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	7/13/2010	NON-COMPETING CONTINUATION	$363,079
														Subtotal = $363,079

Issue Date FY: 2009 ( Subtotal = $448,813 )
2009	2009	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	6/30/2009	NON-COMPETING CONTINUATION	$362,573
2009	2009	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Trans-NIH Recovery Act Research Support	001	7	9/18/2009	SUPPLEMENT FOR EXPANSION	$86,240
														Subtotal = $448,813

Issue Date FY: 2008 ( Subtotal = $362,978 )
2008	2008	INDIANA UNIVERSITY, BLOOMINGTON	BRYAN 215C	BLOOMINGTON	IN	47405	MONROE	USA	Kidney Diseases, Urology and Hematology Research	000	6	9/11/2008	COMPETING CONTINUATION	$362,978
														Subtotal = $362,978

Issue Date FY: 2006 ( Subtotal = $257,971 )
2006	2006	INDIANA UNIVERSITY, BLOOMINGTON	BRYAN 215C	BLOOMINGTON	IN	47405	MONROE	USA	Kidney Diseases, Urology and Hematology Research	000	5	5/10/2006	NON-COMPETING CONTINUATION	$257,971
														Subtotal = $257,971

Issue Date FY: 2005 ( Subtotal = $264,180 )
2005	2005	INDIANA UNIVERSITY, BLOOMINGTON	BRYAN 215C	BLOOMINGTON	IN	47405	MONROE	USA	Kidney Diseases, Urology and Hematology Research	000	4	7/28/2005	NON-COMPETING CONTINUATION	$264,180
														Subtotal = $264,180

Issue Date FY: 2004 ( Subtotal = $288,900 )
2004	2004	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Kidney Diseases, Urology and Hematology Research	000	2	3/29/2004	NON-COMPETING CONTINUATION	$261,564
2004	2004	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Kidney Diseases, Urology and Hematology Research	001	2	4/1/2004	SUPPLEMENT FOR EXPANSION	$27,336
														Subtotal = $288,900

Issue Date FY: 2003 ( Subtotal = $360,580 ) (Continued on the next page)
2003	2003	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Kidney Diseases, Urology and Hematology Research	000	1	5/22/2003	NEW	$322,313
Grand Total All Awards = $8,133,445

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Long-term effects of acute renal failure

Award Number: R01DK063114

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: 07/01/2003

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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