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Mitochondrial regulation of the NLRP3 inflammasome in myocardial ischemia-reperfusion injury and heart transplantation

Award Number: R21AI156919
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/20/2020
PERIOD OF PERFORMANCE END DATE: 10/31/2022

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Mitochondrial regulation of the NLRP3 inflammasome in myocardial ischemia-reperfusion injury and heart transplantation - Project Summary Heart transplantation (HTx) is the only definitive treatment for end-stage heart failure if other medical or surgical treatments and interventions have failed. Despite advances in the management of HTx patients there remains a critical need to optimize long-term outcomes post- HTx. The cumulative risk of death in African-American HTx recipients is particularly high. While racial disparity in outcomes among African-American HTx recipients is well documented, the basis for this difference in is not understood. Mitochondrial DNA (mtDNA) haplogroups reflect an individual's ancestral geographic origin and have been correlated with the disparity in cardiovascular risk observed between Caucasians (haplogroup H) and African-Americans (haplogroup L). An individual's mtDNA haplogroup is known to differentially impact oxidative phosphorylation and consequently mitochondrial efficiency, ATP turnover, and the production of reactive oxygen species and other metabolites. We propose a highly innovate concept that racial differences in mitochondrial function influence the activation of proinflammatory innate immune pathways and subsequent graft failure after HTx. Activation of the NLRP3 inflammasome culminates in the processing and secretion of the proinflammatory cytokine IL-1beta. The NLRP3 inflammasome plays a critical role in driving the pathology associated with ischemia/reperfusion (I/R) injury and targeting this pathway has proven beneficial in both animal models of cardiac I/R injury and in patients with acute myocardial infarction. Minimizing I/R injury is also critical for improving graft survival following HTx. Mitochondria serve as a platform upon which the NLRP3 inflammasome assembles and mitochondrial damage-associated molecular patterns (mito- DAMPs) mediate the priming and activation of the NLRP3 inflammasome. Using the mitochondrial-nuclear exchange (MNX) mouse models, in which isolated embryonic pro-nuclei from one mouse strain are implanted into an enucleated embryo of a different strain, we will assess the importance of functionally distinct mitochondria on the systemic response to ischemic injury. In humans we will interrogate racial disparity in HTx outcomes by examining the impact of mtDNA haplogroups on the response to ischemic injury. Our findings will allow us to identify novel bio-signatures predictive of graft failure allowing for early intervention to limit the NLRP3 inflammasome-dependent pathologic inflammatory response.


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 = $0 )
2023	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	9/27/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $208,750 )
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	10/15/2021	NON-COMPETING CONTINUATION	$208,750
														Subtotal = $208,750

Issue Date FY: 2021 ( Subtotal = $250,500 )
2021	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	11/20/2020	NEW	$250,500
														Subtotal = $250,500

Grand Total All Awards = $459,250

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Mitochondrial regulation of the NLRP3 inflammasome in myocardial ischemia-reperfusion injury and heart transplantation

Award Number: R21AI156919

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 11/20/2020

PERIOD OF PERFORMANCE END DATE: 10/31/2022

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