Thursday, February 19, 2026 2/19/2026

Non-canonical ERAD as a Regulator of Cardiac Hypertrophy

Award Number: R01HL157027
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Non-canonical ERAD as a Regulator of Cardiac Hypertrophy - PROJECT SUMMARY Increases in protein synthesis during pathological cardiac hypertrophy places demands on protein-folding machinery to avert the accumulation of toxic misfolded proteins. Associated with the endoplasmic reticulum (ER), where many important proteins are synthesized in cardiac myocytes, is a system that recognizes and degrades misfolded proteins, i.e. ER associated (protein) degradation, or ERAD. We discovered a different, non-canonical role for ERAD as a regulator of the levels of the growth-promoting kinase, serum glucocorticoid kinase 1 (SGK1). SGK1 is a cytosolic kinase involved in growth of other cell types, such as cancer cells. Interestingly, SGK1 can traffic to the ER where it is ubiquitylated by ERAD machinery and subsequently degraded by cytosolic proteasomes; however, this unique regulatory mechanism has not been studied in the heart. Our preliminary evidence shows that non-canonical ERAD could regulate SGK1 levels in the heart and, thereby regulating cardiac growth under pathological conditions. We also found that an SGK1-binding protein, called glucocorticoid-inducible leucine zipper protein (GILZ), can bind to and protect SGK1 from non-canonical ERAD-mediated degradation, which we believe increases SGK1-mediated growth of the heart during pressure overload. Accordingly, our hypothesis is that SGK1 is a major inducer of pressure overload-induced cardiac pathology. During pressure overload, SGK1 levels, and thus, SGK1-mediated cardiac hypertrophy and subsequent pathology, are increased by GILZ-dependent diversion of SGK1 away from the ER, which decreases SGK1 degradation by non-canonical ERAD. Ectopic expression of an SGK1 peptide disrupts the GILZ-SGK1 interaction, increases SGK1 degradation, thus decreasing SGK1-mediated cardiac hypertrophy and subsequent pathology. This hypothesis will be examined in mice subjected to pressure overload-induced cardiac pathology in our specific aims, which are to 1-couple cardiac-specific SGK1 deletion with AAV9 encoding SGK1-WT (active; ER-targeted), SGK1-KD (kinase-dead ER-targeted) or SGK1-∆60 (active; not ER-targeted) to examine the effect of SGK1 and ERAD on overload-induced cardiac pathology, 2-combine AAV9-SGK1-WT or AAV9- SGK1-∆60 with AAV9-mediated GILZ overexpression or knockdown to determine whether GILZ diverts SGK1- WT from the ER and protects it from ERAD in the heart, 3-evaluate the potential therapeutic, antihypertrophic effects of a novel SGK1 peptide that interrupts GILZ-SGK1 binding, and increases non-canonical ERAD- mediated SGK1 degradation. These studies are significant because they will reveal previously unappreciated roles for SGK1, GILZ and ERAD in pathologic cardiac hypertrophy. We will use an innovative molecular strategy to mechanistically dissect roles for GILZ and non-canonical ERAD as regulators of SGK1 signaling and cardiac pathology. Peptide-based disruption of the SGK1-GILZ interaction could be a highly specific method for inhibiting the maladaptive pathological effects of SGK1 in the heart by selective degradation of SGK1.


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 = $0 )
2026	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	4	11/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $685,917 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	4	12/20/2024	NON-COMPETING CONTINUATION	$553,494
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	003	4	7/31/2025	SUPPLEMENT FOR EXPANSION	$70,924
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	002	4	7/23/2025	NON-COMPETING CONTINUATION	$61,499
2025	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	001	3	6/4/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	004	3	9/5/2025	OTHER REVISION	$0
														Subtotal = $685,917

Issue Date FY: 2024 ( Subtotal = $676,687 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	3	1/11/2024	NON-COMPETING CONTINUATION	$553,494
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	002	3	6/12/2024	NON-COMPETING CONTINUATION	$49,199
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	001	3	1/12/2024	SUPPLEMENT FOR EXPANSION	$73,994
														Subtotal = $676,687

Issue Date FY: 2023 ( Subtotal = $655,060 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	002	2	7/28/2023	SUPPLEMENT FOR EXPANSION	$40,067
2023	2023	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	001	2	3/10/2023	NON-COMPETING CONTINUATION	$61,499
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	003	2	9/20/2023	SUPPLEMENT FOR EXPANSION	-$40,067
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	004	2	9/22/2023	SUPPLEMENT FOR EXPANSION	$40,067
2023	2023	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	2	1/2/2023	NON-COMPETING CONTINUATION	$553,494
														Subtotal = $655,060

Issue Date FY: 2022 ( Subtotal = $614,993 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	1	12/27/2021	NEW	$614,993
														Subtotal = $614,993

Grand Total All Awards = $2,632,657

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Non-canonical ERAD as a Regulator of Cardiac Hypertrophy

Award Number: R01HL157027

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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