Wednesday, November 29, 2023 11/29/2023

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)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

Gram-negative sepsis remains a major cause of mortality and morbidity in hospitalized patients, especially when complicated by acute kidney injury (AKI). The pathophysiology of AKI in sepsis continues to be poorly understood resulting in the persistent failure of clinical therapeutic trials. Recently, we identified a novel pathway of renal injury in sepsis involving direct interactions between filtered endotoxin and S1 proximal tubules. This endotoxin-S1 interaction resulted in severe peroxisomal damage and oxidative stress in downstream S2 and S3 segments. Remarkably, this pathway of injury had no requirement for competent immune cells. In this proposal, we continue our investigation of sepsis and AKI by examining the mechanisms of renal endotoxin preconditioning. The phenomenon of protective preconditioning is unique in that it represents a state of resistance to the deleterious effects of endotoxin and yet, a preserved ability to effectively contain and eliminate infections. Unraveling the pathways involved in endotoxin tolerance has great potential for identifying potential targets that can be used for the prevention and treatment of human sepsis. Historically, preconditioning has been investigated in immune cells and their isolated responses to repeated endotoxin exposure. Little is known about the mechanisms leading to tissue protection in whole organs such as the kidney. Based on strong preliminary data, the central hypothesis of this proposal is that macrophages are essential components of the protective pathways of preconditioning. This is a novel hypothesis because it depicts the macrophage as an active and beneficial participant in the tolerant phenotype. In specific aim 1, we will establish the essential role of macrophages and examine their cross-talk with renal tubules such as the S1 segment. In specific aim 2, we will determine the metabolic and transcriptomic changes imparted by protective macrophages on S1 tubules. We will also identify key metabolites that can be used directlt to treat sepsis. In specific aim 3, we will examine the potential of protective macrophages to treat sepsis in a cell transfer approach. We believe that the proposed studies, by increasing our understanding of endotoxin preconditioning, have great translational potential and will uncover a novel and global approach to the prevention and treatment of sepsis and sepsis-induced AKI.


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 = $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


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	000	6	6/24/2022	COMPETING CONTINUATION	$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


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


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


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


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


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


Grand Total All Awards = $2,847,231

Sum of Action Amount is $2,847,231;

Grand Total = $2,847,231

Top

All Categories

About

Search

Reports

Data Submission

Award Information

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)

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer