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Endotoxin preconditioning as a model to uncover protective pathways in sepsis-induced renal injury

Award Number: R01DK107623
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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Endotoxin preconditioning as a model to uncover protective pathways in sepsis-induced renal injury - Sepsis-induced acute kidney injury remains a major clinical problem with no effective therapy established to date. Although potential therapeutic targets have been identified and tested in clinical trials, none of them has proven to be effective, underscoring the complexity of sepsis pathophysiology. Work from our laboratory identified disturbances in cell-cell communication as a major feature underlying the complex pathophysiology of sepsis-induced kidney damage. For example, pathologic signaling from S1 tubules to downstream S2/S3 tubules was a major pathway of renal injury in sepsis. Indeed, we identified the S1 proximal tubular segment as a major sensor and sink for filtered endotoxin. This S1 uptake of endotoxin resulted in severe oxidative stress and damage to downstream S2/S3 segments. Targeted S1 transcriptomics and tissue metabolomics revealed that purine metabolism is markedly altered in septic S1 proximal tubules. This shift is catalyzed by xanthine oxidoreductase, a key enzyme in the purine degradation pathway. This enzyme functions as a dehydrogenase (XDH) in its native form but is readily converted to an oxidase (XO) through sulfhydryl oxidation or proteolytic modification. Whereas catalysis by XDH does not generate free radicals, XO is a strong pro-oxidant that generates deleterious reactive species. Furthermore, the pro-oxidant XO is secreted into the urinary lumen and can therefore cause damage to downstream segments. In contrast, XO expression in macrophages may be beneficial because it stimulates the bactericidal potential of these cells through generation of reactive species. It is one goal of this proposal to establish the relative roles of XO versus XDH in S1 and macrophages in septic kidneys. Moreover, because XO/XDH is involved in the final degradation of purines, the changes in XO/XDH activity will not only affect the generation of reactive species but will also have an upstream impact on the size of purine pools. It is the second goal of this proposal to determine the overall flux of purine metabolites and their contributions to purine homeostasis in sepsis.


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 = $513,156 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	7/24/2024	NON-COMPETING CONTINUATION	$513,156
2024	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $513,156

Issue Date FY: 2023 ( Subtotal = $534,538 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	6/16/2023	NON-COMPETING CONTINUATION	$534,538
														Subtotal = $534,538

Issue Date FY: 2022 ( Subtotal = $534,538 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	7/22/2022	COMPETING CONTINUATION	$0
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	6/24/2022	COMPETING CONTINUATION	$534,538
														Subtotal = $534,538

Issue Date FY: 2020 ( Subtotal = $375,100 )
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/18/2020	NON-COMPETING CONTINUATION	$375,100
														Subtotal = $375,100

Issue Date FY: 2019 ( Subtotal = $375,100 )
2019	2019	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/20/2019	NON-COMPETING CONTINUATION	$375,100
														Subtotal = $375,100

Issue Date FY: 2018 ( Subtotal = $375,100 )
2018	2018	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/16/2018	NON-COMPETING CONTINUATION	$375,100
														Subtotal = $375,100

Issue Date FY: 2017 ( Subtotal = $281,327 )
2017	2017	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/22/2017	NON-COMPETING CONTINUATION	$281,327
														Subtotal = $281,327

Issue Date FY: 2016 ( Subtotal = $371,528 )
2016	2016	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/24/2016	NEW	$371,528
														Subtotal = $371,528

Grand Total All Awards = $3,360,387

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Endotoxin preconditioning as a model to uncover protective pathways in sepsis-induced renal injury

Award Number: R01DK107623

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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