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Fatty acid metabolism in disease models of mitochondrial fatty acid synthesis deficiency.

Award Number: R21HD114905
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: 08/04/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Fatty acid metabolism in disease models of mitochondrial fatty acid synthesis deficiency. - Title: Fatty acid metabolism in disease models of mitochondrial fatty acid synthesis deficiency Project summary/abstract: Rare genetic diseases cause 35% of deaths in children under 1 year of age and are a significant cause of pediatric hospital admissions. Primary mitochondrial diseases are one group of inborn errors of metabolism (IEM) caused by germline mutations in genes involved in metabolism. While individually rare, IEMs collectively affect 1 in 5,000 children making them relatively common as a group. Despite their prevalence, mitochondrial disorders are difficult to diagnose and treat, in part because of our often-poor understanding of the underlying molecular etiology. Deficiencies in the mitochondrial fatty acid synthesis (mtFAS) pathway are an emerging group of childhood-onset mitochondrial diseases with particularly understudied pathophysiology. Genetic variants in mtFAS genes cause Mitochondrial enoyl reductase Protein Associated Neurodegeneration (MePAN) syndrome, which presents with severe developmental delays, seizures, hypotonia, hearing and vision loss, and a plethora of systemic problems. mtFAS produces both lipoic acid (an important co-factor for several enzymes) and long-chain fatty acids that support electron transport chain function. However, the cellular roles of mtFAS products and the pathway’s function in diverse cellular contexts are still unclear, preventing the development of rationale-based therapies for mtFAS deficiency. To better treat MePAN syndrome, we need new approaches. Toward this overarching goal, we will use two complementary methodologies to identify potential therapeutic targets that rescue growth and development in mtFAS-deficient patient models. We have developed a novel, organismal model of MePAN syndrome by recreating patient mutations in Caenorhabditis elegans, which result in marked developmental delays. We show that we can use this model to perform genome-wide screens in whole organisms, and successfully recover genetic suppressors of the phenotypes caused by mtFAS patient variants. In parallel, we have performed preliminary CRISPR/Cas9 screens in mtFAS-deficient cells and found that loss of fatty acid oxidation pathway genes, as well as genes encoding subunits of the mitochondrial electron transport chain, rescues growth in mtFAS-deficient cells. We propose to test the utility of these findings in a panel of primary patient fibroblasts, and to expand our analyses by performing genome wide loss of function and CRISPRa screens to identify additional pathways of suppression. Together, these experiments will lay the groundwork for future development of therapeutics for mtFAS-deficient patients and their families.


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 = $240,000 )
2026	2026	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Child Health and Human Development Extramural Research	000	2	8/4/2026	NON-COMPETING CONTINUATION	$240,000
														Subtotal = $240,000

Issue Date FY: 2025 ( Subtotal = $288,000 )
2025	2025	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Child Health and Human Development Extramural Research	001	1	8/4/2025	NEW	$0
2025	2025	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Child Health and Human Development Extramural Research	000	1	8/4/2025	NEW	$288,000
														Subtotal = $288,000

Grand Total All Awards = $528,000

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Fatty acid metabolism in disease models of mitochondrial fatty acid synthesis deficiency.

Award Number: R21HD114905

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: 08/04/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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