Sunday, July 6, 2025 7/6/2025

Regulation of ER homeostasis by TCA cycle activity: mechanisms and consequences

Award Number: R01GM115424
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2015
PERIOD OF PERFORMANCE END DATE: 06/30/2024

Group Awards By:

View Award Description

Regulation of ER homeostasis by TCA cycle activity: mechanisms and consequences - Project Summary Disruption of protein folding in the endoplasmic reticulum—“ER stress”—is associated with many different metabolic diseases, particularly those associated with obesity that affect between 22 and 30 percent of adults in the U.S. Because of this exceptional disease burden, it is important to understand the factors that cause ER stress during metabolic dysregulation. Yet the pathways by which metabolic activity and ER homeostasis are coupled are poorly understood. Mitochondria are central to metabolism, and the TCA cycle is the hub of this activity, accepting substrates from glycolysis and fatty acid oxidation for catabolism, generating reducing equivalents for electron transport and for the maintenance of cellular redox homeostasis, and providing building materials for the reductive biosynthesis of lipids, glucose, and amino acids. Because of its centrality to so many processes, flux through the TCA cycle is likely to affect many diverse cellular pathways, even those with no obvious direct connection. This includes ER protein processing, which is sensitive to changes in redox state, amino acid availability, and cellular lipid content. In the parent proposal, we provide evidence for a previously unknown functional relationship between TCA cycle activity and ER homeostasis in metabolically active cells, including hepatocytes, myocytes, and adipocytes, that depends on production of NADPH by the TCA cycle and redox regulation of glutathione. This proposal is designed to identify the basic mechanisms linking TCA-dependent NADPH production in the mitochondria to homeostasis in the ER. Toward that end, we propose three specific aims: (1) Determine how NADPH production and compartmentalization link nutrient flow to ER stress; (2) Determine how changes to mitochondrial and cytosolic glutathione redox promote ER oxidation; and (3) Determine how TCA activity and glutathione redox alter ER function. We will achieve these aims using a combination of genetic and pharmacological tools to manipulate TCA cycle activity; cutting-edge biosensors to monitor changes in cellular redox status; manipulation and analysis of ER-mitochondrial contacts; and molecular biology approaches to manipulate and assess ER functionality. The outcome of this work will be a mechanistic understanding of how metabolic activity alters ER function to contribute to disease. This supplemental application requests funds to support an immersive summer research experience for an undergraduate who has worked part-time in the Rutkowski lab over the last year.


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: 2025 ( Subtotal = -$1,725 )
2025	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	000	8	3/5/2025	NON-COMPETING CONTINUATION	-$1,510
2025	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	001	8	3/5/2025	SUPPLEMENT FOR EXPANSION	-$164
2025	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	002	7	3/5/2025	SUPPLEMENT FOR EXPANSION	-$51
														Subtotal = -$1,725

Issue Date FY: 2023 ( Subtotal = $363,489 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	002	8	8/23/2023	SUPPLEMENT FOR EXPANSION	$34,458
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	000	7	5/11/2023	SUPPLEMENT FOR EXPANSION	$10,761
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	001	8	7/3/2023	NON-COMPETING CONTINUATION	$318,270
														Subtotal = $363,489

Issue Date FY: 2022 ( Subtotal = $318,270 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	000	7	6/20/2022	NON-COMPETING CONTINUATION	$318,270
														Subtotal = $318,270

Issue Date FY: 2021 ( Subtotal = $318,270 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	001	6	7/1/2021	NON-COMPETING CONTINUATION	$318,270
2021	2018	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	000	4	6/4/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $318,270

Issue Date FY: 2020 ( Subtotal = $318,270 )
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	000	5	8/25/2020	COMPETING CONTINUATION	$318,270
														Subtotal = $318,270

Issue Date FY: 2018 ( Subtotal = $301,188 )
2018	2018	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	000	4	6/22/2018	NON-COMPETING CONTINUATION	$301,188
														Subtotal = $301,188

Issue Date FY: 2017 ( Subtotal = $301,188 )
2017	2017	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	000	3	6/14/2017	NON-COMPETING CONTINUATION	$301,188
														Subtotal = $301,188

Issue Date FY: 2016 ( Subtotal = $301,188 )
2016	2016	UNIVERSITY OF IOWA	2 GILMORE HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	000	2	5/31/2016	NON-COMPETING CONTINUATION	$301,188
														Subtotal = $301,188

Issue Date FY: 2015 ( Subtotal = $298,225 )
2015	2015	UNIVERSITY OF IOWA	2 GILMORE HALL	IOWA CITY	IA	52242	JOHNSON	USA	Biomedical Research and Research Training	000	1	8/24/2015	NEW	$298,225
														Subtotal = $298,225

Grand Total All Awards = $2,518,363

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Regulation of ER homeostasis by TCA cycle activity: mechanisms and consequences

Award Number: R01GM115424

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2015

PERIOD OF PERFORMANCE END DATE: 06/30/2024

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer