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Reductive Stress Induces Proteotoxic Cardiac Disease

Award Number: R01HL118067
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/29/2013
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Reductive Stress Induces Proteotoxic Cardiac Disease - Conventionally, oxidative stress is considered pathological to cardiac protein quality control (PQC), which rationalizes the therapeutic potential of antioxidants. However, many clinical trials of antioxidant supplementation failed to deliver a positive impact and, rather, demonstrated adverse effects in various organs, including those in the cardiovascular system. Emerging evidence suggests that reductive stress (RS), also known as antioxidative stress, may cause ER stress and accumulation of mis/unfolded proteins. To fully comprehend the molecular interplay underlying RS-mediated proteotoxicity and the time frame for myocardium experiencing a transition from adaptive to maladaptive remodeling, it is critical to identify the molecular participants, their dynamic interplay, and resulting sequential events (e.g., autophagy) that regulate PQC. Recently, our exciting and novel clinical observations revealed a link of chronic RS (cRS) underlying disease progression of human heart failure (HF). We screened a selected group of HF patients (n=50, without other major comorbidities) for their peripheral blood redox state; among them, a subset (n=8) displayed the RS condition. Our proposed study will entail a translational component utilizing proteomics approaches and molecular biology to better understand the etiology of RS in mouse models and to identify its relevance in HF patients. Our central hypothesis is that cRS will alter proteome properties (e.g., protein dynamics & post- translational modifications, or PTMs) and damage autophagy signaling, leading to persistent proteotoxicity and cardiac dysfunction, thereby driving maladaptive remodeling in animal models and in human heart diseases. We propose three aims: Aim 1 will determine altered protein dynamics, redistributed PTMs, and perturbed autophagy subproteome in RS conditions. We will define the “reductome signatures” in control and cRS phenotypes. Aim 2 will examine the impact of cRS on progressive damage of autophagy that may lead to insufficient cargo-clearance and proteotoxicity in the myocardium over time. We will assess autophagosome formation, autophagy flux, and protein folding capacity under cRS conditions and examine whether enhancing autophagy delays and/or prevents proteotoxicity in mice. Aim 3 will examine the “redox phenotype” in the peripheral blood of HF patients using HPLC based quantification of (a) GSH redox ratio, (b) lipid peroxidation, and (c) total antioxidant capacity, as well as extract the molecular “reductome signatures” in HF patients with RS using a computational platform to determine essential proteome features and regulatory pathways. This aim will establish a translational value for the RS hypothesis in human HF. We have assembled a multidisciplinary team (scientists & physicians) with documented expertise in redox biology, biochemistry, proteomics, and computational analyses. The genetic mouse models of RS, the technology platforms, and the biochemical assays to evaluate RS in mouse and in human are all established in our laboratories. We anticipate the successful completion of our proposed goals.


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 = -$1,423 )
2026	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	9	12/18/2025	NON-COMPETING CONTINUATION	-$1,423
														Subtotal = -$1,423

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	9	6/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	9	6/29/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $581,744 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	9	7/21/2021	NON-COMPETING CONTINUATION	$581,744
														Subtotal = $581,744

Issue Date FY: 2020 ( Subtotal = $582,126 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	8	7/25/2020	NON-COMPETING CONTINUATION	$582,126
														Subtotal = $582,126

Issue Date FY: 2019 ( Subtotal = $954,881 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	003	7	8/28/2019	SUPPLEMENT FOR EXPANSION	$374,715
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	002	7	8/8/2019	NON-COMPETING CONTINUATION	$580,166
2019	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	6	11/13/2018	COMPETING CONTINUATION	$165,684
2019	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	5	11/13/2018	NON-COMPETING CONTINUATION	-$165,684
														Subtotal = $954,881

Issue Date FY: 2018 ( Subtotal = $594,251 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	6	7/27/2018	COMPETING CONTINUATION	$594,251
2018	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	5	7/25/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $594,251

Issue Date FY: 2017 ( Subtotal = $368,275 )
2017	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	5	7/13/2017	NON-COMPETING CONTINUATION	$368,275
														Subtotal = $368,275

Issue Date FY: 2016 ( Subtotal = $368,275 )
2016	2016	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	6/13/2016	NON-COMPETING CONTINUATION	$368,275
														Subtotal = $368,275

Issue Date FY: 2015 ( Subtotal = $362,750 )
2015	2015	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	3	7/9/2015	NON-COMPETING CONTINUATION	$362,750
														Subtotal = $362,750

Issue Date FY: 2014 ( Subtotal = $365,024 )
2014	2014	UNIVERSITY OF ALABAMA AT BIRMINGHAM	1530 3rd Avenue South, AB 1170	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	2	8/11/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$365,024
														Subtotal = $365,024

Issue Date FY: 2013 ( Subtotal = $364,082 )
2013	2013	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	000	1	7/28/2013	NEW	$364,082
														Subtotal = $364,082

Grand Total All Awards = $4,539,985

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Reductive Stress Induces Proteotoxic Cardiac Disease

Award Number: R01HL118067

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/29/2013

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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