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Rapamycin as a potential treatment for succinate dehydrogenase deficiency

Award Number: R15GM113156
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2015
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Rapamycin as a potential treatment for succinate dehydrogenase deficiency - Rapamycin is an inhibitor of the mechanistic Target of Rapamycin pathway (mTOR). This drug has anti-carcinogenic and pro-longevity characteristics. We, and others, have shown that rapamycin could also be considered as a treatment for mitochondrial disorders since feeding rapamycin to genetic models for mitochondrial disorders improve the pathology associated with the diseases. However, resistance to rapamycin hinders the efficacy of such treatment. Molecular genetic analysis in D. melanogaster provides unique approaches to uncover the basic mechanism of insensitivity of rapamycin. In this context, we have discovered that introgressed strains of Drosophila harboring mitochondrial DNA form D. simulans in a D. melanogaster nuclear DNA do not respond to rapamycin treatment while wild type D. melanogaster or wild type D. simulans respond to the drug. In addition, we discovered that rapamycin beneficial effect on mitochondrial function requires a shift of metabolism, in particular, the catabolism of proteins. Wild type D. melanogaster fed a diet rich on proteins, or lacking proteins do not respond to the increase on metabolic rate mediated by rapamycin. Metabolomics analysis and preliminary molecular genetics analysis with mutants for the glutamate dehydrogenase, the enzyme that catabolize glutamate into alpha-ketoglutarate, have identified the critical role of the glutamine, glutamate and alpha-ketoglutarate anapleourotic (Gln-Glu-αKG) pathway in the response to rapamycin. Based on our observations and the documented effects of the sensitivity and the resistance to rapamycin, in this proposal we will test the hypothesis that rapamycin sensitivity depends upon the qualitative used of the Gln-Glu-αKG pathway by the cell. To test this hypothesis, we will use a combination of introgressed mitochondrial DNAs strains, with and without mutations on genes that codify for several members of the the Gln-Glu-αKG pathway. We will study the sensitivity and resistance to rapamycin treatment by exposing the aforementioned strains to rapamycin treatment in the presence and absence of amino acids supplementation. We will complement those analyses with metabolomics assays that will depict the metabolic space of the resistance to rapamycin. Overall, this proposal aims to identified the hallmarks of the insensitivity to rapamycin treatment using a unique set of tools provided with the use of mitochondria introgressed strains.


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 = -$81,286 )
2026	2021	ADELPHI UNIVERSITY	1 SOUTH AVE # 304	GARDEN CITY	NY	11530	NASSAU	USA	Biomedical Research and Research Training	000	2	2/19/2026	COMPETING CONTINUATION	-$81,286
														Subtotal = -$81,286

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	ADELPHI UNIVERSITY	1 SOUTH AVE # 304	GARDEN CITY	NY	11530	NASSAU	USA	Biomedical Research and Research Training	000	2	6/26/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $352,428 )
2021	2021	ADELPHI UNIVERSITY	1 S AVE LVH 310	GARDEN CITY	NY	11530	NASSAU	USA	Biomedical Research and Research Training	000	2	7/23/2021	COMPETING CONTINUATION	$352,428
														Subtotal = $352,428

Issue Date FY: 2019 ( Subtotal = -$3,925 )
2019	2015	ADELPHI UNIVERSITY	1 S AVE	GARDEN CITY	NY	11530	NASSAU	USA	Biomedical Research and Research Training	000	1	8/28/2019	NEW	-$3,925
														Subtotal = -$3,925

Issue Date FY: 2015 ( Subtotal = $242,687 )
2015	2015	ADELPHI UNIVERSITY	S AVENUE,LEVERMORE HALL-RM 203	GARDEN CITY	NY	11530	NASSAU	USA	Biomedical Research and Research Training	000	1	3/3/2015	NEW	$242,687
														Subtotal = $242,687

Grand Total All Awards = $509,904

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Rapamycin as a potential treatment for succinate dehydrogenase deficiency

Award Number: R15GM113156

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2015

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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