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Roles of SARM1 NAD hydrolase in metabolic cardiomyopathy

Award Number: R01HL164854
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/05/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Roles of SARM1 NAD hydrolase in metabolic cardiomyopathy - NAD+ depletion is observed in diseases including heart failure and metabolic cardiomyopathy. Maintaining NAD+ homeostasis by activating NAD+ synthesis pathways has shown great promise to treat diseases. We here explore that inhibiting NAD+ consumption will prevent NAD+ depletion and ameliorate heart disease. NAD+ hydrolases catalyze NAD+ degradation to form nicotinamide and ADPR. SARM1 is an intracellular NAD+ hydrolase that is known as an executer of axonal degeneration and promotes mitochondrial dysfunction. Recent studies showed that SARM1 is activated by increased NMN/NAD+ ratio and SARM1 phosphorylation. However, the role of SARM1 in metabolic cardiomyopathy has never been reported, and how SARM1 is activated to cause mitochondrial dysfunction is not known. The overall objective of this project is to investigate how SARM1 promotes NAD+ decline and regulates mitophagy during metabolic cardiomyopathy. Further understanding of SARM1 in the heart will lead to a new target for therapeutic development of heart disease. In our pilot data, we showed that SARM1 deficiency in SARM1-KO mice and in newly developed cardiomyocyte-specific SARM1-KO mice (SARM1-cKO) protected against metabolic stress-induced cardiomyopathy, providing the first evidence on the role of SARM1 in causing dysfunction of diabetic hearts. Pilot data further suggested that NAD+ metabolic and JNK1 phosphorylation signaling may activate SARM1, and SARM1 promotes mitophagy in diabetic hearts. Based on these results, we propose to dissect the pathogenic mechanisms of SARM1 in metabolic cardiomyopathy with the three aims. Specific Aim 1 will use SARM1-cKO mice to determine the impact of cardiomyocyte SARM1 deficiency on type 1 diabetes (T1D)- induced and diet-induced obesity (DIO)-induced cardiomyopathy. Multi-omics analyses targeting known mechanistic pathways of diabetic hearts will be performed to identify how cardiomyocyte SARM1 deficiency protects hearts against the two types of metabolic stresses. Specific Aim 2 will understand how metabolic stress activates SARM1 to cause compartmental NAD+ decline. We will manipulate NAD+ metabolic and JNK1- SARM1 phosphorylation signaling to establish how the two pathways activate SARM1 to cause NAD+ decline in mitochondria or cytosol using compartment-specific NAD+ biosensors. Specific Aim 3 will determine how SARM1 promotes mitophagy in diabetic hearts. Mitophagy flux impacted by metabolic stress and SARM1 deficiency will be measured by mito-Keima mice. How SARM1 promotes mitophagy via traditional PINK1- Parkin and/or alternative Ulk1-Rab9 pathways will be examined in diabetic hearts. This project will establish SARM1 as a new target to promote NAD+ decline mitochondrial dysfunction and metabolic cardiomyopathy. The results from this project will identify new therapeutic targets linked to SARM1-dependent mechanisms.


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 = $604,146 )
2026	2026	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	4	7/9/2026	NON-COMPETING CONTINUATION	$604,146
														Subtotal = $604,146

Issue Date FY: 2025 ( Subtotal = $616,475 )
2025	2025	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	3	7/23/2025	NON-COMPETING CONTINUATION	$616,475
														Subtotal = $616,475

Issue Date FY: 2024 ( Subtotal = $604,146 )
2024	2024	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	2	6/7/2024	NON-COMPETING CONTINUATION	$604,146
														Subtotal = $604,146

Issue Date FY: 2023 ( Subtotal = $634,100 )
2023	2023	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	1	6/5/2023	NEW	$634,100
														Subtotal = $634,100

Grand Total All Awards = $2,458,867

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Roles of SARM1 NAD hydrolase in metabolic cardiomyopathy

Award Number: R01HL164854

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/05/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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