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Targeting Immune-Responsive Gene 1 (Irg1) and Itaconate for Cardioprotection of the Donor Heart for Transplantation

Award Number: R01HL164416
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Targeting Immune-Responsive Gene 1 (Irg1) and Itaconate for Cardioprotection of the Donor Heart for Transplantation - Heart transplantation is considered gold standard therapy for end-stage heart failure. However, demand currently far outstrips supply due to multiple challenges. An important limitation is the occurrence of primary graft dysfunction (PDG) in 10-20% of patients and contributes greatly to adverse clinical outcomes and resource utilization. PGD occurs when donor heart function and output is inadequate end organ perfusion. Risk for significant PDG increases when donor heart preservation time is greater than 4 hours. Valproic acid (VPA), a histone deacetylase inhibitor, is a “Food and Drug Administration (FDA)” approved drug traditionally used for the treatment of epilepsy. We now convincingly demonstrate that addition of VPA can dramatically improve donor heart function and improve ischemic tolerance compared to preservation using Histidine-Tryptophan- Ketoglutarate (HTK) preservation solution alone. This was seen in murine heart reperfusion models in the setting of ex-vivo perfusion and transplantation. Furthermore, we show evidence that VPA achieves this by upregulating tricarboxylic acid cycle enzyme Irg1 which produces the anti-inflammatory metabolite “itaconate”. Indeed, our cardiac reperfusion model confirms the impressive upregulation of Irg1 above baseline driven by VPA treatment, and this was accompanied by robust activation of antioxidant pathway mechanisms through Nrf2 transcription factor. Chromatin immunoprecipitation showed that VPA treatment increased Irg1 enhancer activity as indicated by increased occupancy by acetylated H3K27 histone. Importantly, VPA treatment of stored human donor hearts also upregulated Irg1 expression and decreased the expression of inflammatory mediators suggesting translational relevance for large animal and human clinical settings. For this proposal, we plan to: (1) Identify the cell type through which Irg1 acts and we hypothesize that it is most likely through cardiomyocytes (CM) and endothelial cells (EC). The is achieved using transgenic mice with conditional deficiency of Irg1 in these cell types using inducible Cre-Lox technology. We will also examine overexpression models using adeno-associated virus mediated expression Irg1 mRNA. (2) Using cell culture, we will determine whether Irg1/itaconate mediated alkylation modifications on Nrf2 pathway antioxidant proteins impacts their function. We will treat cells with itaconate and then identify as well as mutate relevant alkylation modifications sites at the cysteine residue of antioxidant proteins to determine their importance. (3) We will determine the efficacy of VPA for improving donor heart function and ischemic tolerance in pigs and humans. We will also corroborate mechanisms of VPA mediated cardioprotection identified in murine models. This project has critical clinical implications such as decreasing the PGD incidence, allow transport of donor hearts over longer distances to facilitate organ allocation, and improve clinical transplantation outcomes. Reduction in perioperative donor heart injury by harnessing the cardioprotective effect of VPA and Irg1/itaconate is novel and potentially relevant for preservation of other organs such as the livers and kidneys.


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 = $647,639 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	002	4	7/29/2025	NON-COMPETING CONTINUATION	$647,639
2025	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	001	2	2/19/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$19,824
2025	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	1	2/19/2025	NEW	-$19,824
														Subtotal = $647,639

Issue Date FY: 2024 ( Subtotal = $638,627 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	001	3	7/18/2024	NON-COMPETING CONTINUATION	$638,627
2024	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	000	2	10/20/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $638,627

Issue Date FY: 2023 ( Subtotal = $670,914 )
2023	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	001	2	8/11/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$670,914
2023	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	1	8/9/2023	NEW	$0
														Subtotal = $670,914

Issue Date FY: 2022 ( Subtotal = $690,954 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Cardiovascular Diseases Research	000	1	6/14/2022	NEW	$690,954
														Subtotal = $690,954

Grand Total All Awards = $2,648,134

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Targeting Immune-Responsive Gene 1 (Irg1) and Itaconate for Cardioprotection of the Donor Heart for Transplantation

Award Number: R01HL164416

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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