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Metabolic regulation of MODS in pediatric mitochondrial disorders

Award Number: R01HD110536
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
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: 05/31/2028

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Metabolic regulation of MODS in pediatric mitochondrial disorders - PROJECT SUMMARY Devastating human primary mitochondrial disorders are caused by pathogenic mtDNA variants and frequently evolve into organ failures referred to, as mitochondrial-induced multiple organ dysfunction syndrome (MIMODS). The underlying pathophysiologic mechanisms are more complex than a mere decrease in ATP pro- duction and very little is known about these complex processes in a tissue-specific manner. There is thus an urgent unmet need to assess the impact of the widespread mitochondrial dysfunction in multiple tissues leading to MIMODS. We have demonstrated deleterious outcomes of widespread mitochondrial dysfunction (lowered bioenergetics health index, abnormal mitochondrial morphology, elevated putrescine levels) in multiple pediat- ric PMD dermal fibroblasts carrying unique pathogenic mtDNA variants. Based on our findings, we hypothesize that elevated putrescine levels cause oxidative stress response and widespread mitochondrial dysfunction that contributes to MIMODS in cellular models of primary mitochondrial disorders. Our collaborative team will de- sign experiments and build upon established expertise in mitochondrial genetics and physiology, stem cell biol- ogy and differentiation, next-generation sequencing analysis and metabolite profiling to address the following research aims: In Aim 1, we will comprehensively assess mitochondrial dysfunction in twenty pediatric diseased fibroblasts with a confirmed diagnosis of PMDs, along with five age matched controls. We will assess the oxida- tive stress markers, NAD/NADH redox biochemistry, metabolomics, mitochondrial respiration and morphology. In aim 2, we will seek to understand tissue-specific abnormalities associated with mitochondrial dysfunction in neurons, cardiomyocytes and podocytes. In aim 3, we will assess the effect of targeted interventions of reducing oxidative stress and improving mitochondrial respiration in multiple differentiated cell types that exhibit ele- vated putrescine levels; and in multiple tissues from preclinical mouse models of PMD. The completion of these aims will contribute to a newer understanding of putrescine metabolism in multiple energy-intensive cell types derived from patients with pediatric PMD and its role in triggering MIMODS. In the long-term, our studies have the potential to develop strategies for individualized testing of patient cells with candidate therapeutics to drive rational, personalized therapies.


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 = $613,390 )
2025	2025	UNIVERSITY OF ARKANSAS	1125 W MAPLE ST STE 316	FAYETTEVILLE	AR	72701	WASHINGTON	USA	Child Health and Human Development Extramural Research	000	3	4/29/2025	NON-COMPETING CONTINUATION	$613,390
														Subtotal = $613,390

Issue Date FY: 2024 ( Subtotal = $611,953 )
2024	2024	UNIVERSITY OF ARKANSAS	1125 W MAPLE ST STE 316	FAYETTEVILLE	AR	72701	WASHINGTON	USA	Child Health and Human Development Extramural Research	000	2	5/28/2024	NON-COMPETING CONTINUATION	$611,953
														Subtotal = $611,953

Issue Date FY: 2023 ( Subtotal = $673,530 )
2023	2023	UNIVERSITY OF ARKANSAS SYSTEM	1125 WEST MAPLE STE 210	FAYETTEVILLE	AR	72701	WASHINGTON	USA	Child Health and Human Development Extramural Research	000	1	7/31/2023	NEW	$673,530
														Subtotal = $673,530

Grand Total All Awards = $1,898,873

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Metabolic regulation of MODS in pediatric mitochondrial disorders

Award Number: R01HD110536

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

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: 05/31/2028

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