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Coordinated Repair and Regeneration of Defective Mitochondria

Award Number: R37AG047182
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2015
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Coordinated Repair and Regeneration of Defective Mitochondria - Project Summary Mitochondrial function declines during aging and is accelerated in age-associated diseases such as Parkinson's and Alzheimer's. Thus, understanding how cells and organisms generate the appropriate mitochondrial mass during development and maintain that mitochondrial network during aging is an essential step to limiting pathologies associated with loss of mitochondrial function. Here, we aim to understand the underlying mechanisms by which the transcription factor ATFS-1 and the mitochondrial unfolded protein response (UPRmt) coordinate mitochondrial network biogenesis during normal development and the recovery of the mitochondrial network via independently regulated functions of ATFS-1 in mitochondrial compartments and the nucleus. Numerous components have been identified that promote replication of the mitochondrial genome and transcription of nuclear-encoded genes that result in mitochondrial biogenesis. However, it remains unclear how the appropriate amount of mitochondrial mass is achieved during development or cell specification, and how the mitochondrial network is maintained over a cell or organisms lifetime. It also remains unknown if mitochondrial genome (mtDNA) replication is coordinated with cell growth, physiology, or functional heterogeneity within the compartments that comprise the mitochondrial network. Current dogma suggests that mtDNA replication is entirely dependent on expression of several nuclear-encoded factors such as the mtDNA polymerase. Despite functional heterogeneity within the mitochondrial network, compartment-specific autonomy over mtDNA regulation is rarely considered. In this proposal, we aim to understand how ATFS-1 establishes the appropriate amount mitochondrial mass during development, and maintains the mitochondrial network over an animals lifetime focusing on the separate activities of nuclear ATFS-1, and the fraction of ATFS-1 that accumulates in dysfunctional mitochondria and binds mtDNA. Lastly, we aim to understand the impact of an ATFS-1-mediated diapause that occurs if the mitochondrial network is severely damaged during development. At the end of the funding period, we hope to understand the endogenous strategies in place to establish and maintain the mitochondrial network, to potentially develop strategies to promote or maintain a robust mitochondrial network.


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 = $515,232 )
2026	2026	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	000	12	4/3/2026	NON-COMPETING CONTINUATION	$515,232
														Subtotal = $515,232

Issue Date FY: 2025 ( Subtotal = $504,927 )
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	002	11	6/10/2025	EXTENSION WITH OR WITHOUT FUNDS	$41,218
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	000	11	5/2/2025	EXTENSION WITH OR WITHOUT FUNDS	$463,709
2025	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	001	10	5/21/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $504,927

Issue Date FY: 2024 ( Subtotal = $446,523 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	001	10	6/11/2024	NON-COMPETING CONTINUATION	$44,651
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	000	10	2/7/2024	NON-COMPETING CONTINUATION	$401,872
														Subtotal = $446,523

Issue Date FY: 2023 ( Subtotal = $605,597 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	002	9	2/24/2023	NON-COMPETING CONTINUATION	$446,523
2023	2020	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	001	6	10/12/2022	COMPETING CONTINUATION	$8,753
2023	2020	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	000	6	10/12/2022	COMPETING CONTINUATION	$150,321
														Subtotal = $605,597

Issue Date FY: 2022 ( Subtotal = $446,523 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	001	8	5/5/2022	NON-COMPETING CONTINUATION	$44,650
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	000	8	2/2/2022	NON-COMPETING CONTINUATION	$401,873
														Subtotal = $446,523

Issue Date FY: 2021 ( Subtotal = $292,082 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	000	7	3/15/2021	NON-COMPETING CONTINUATION	$442,403
2021	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	001	6	5/19/2021	COMPETING CONTINUATION	-$150,321
														Subtotal = $292,082

Issue Date FY: 2020 ( Subtotal = $605,597 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	002	6	5/19/2020	COMPETING CONTINUATION	$159,074
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	001	6	3/19/2020	COMPETING CONTINUATION	$0
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Aging Research	000	6	1/8/2020	COMPETING CONTINUATION	$446,523
														Subtotal = $605,597

Grand Total All Awards = $3,416,481

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Coordinated Repair and Regeneration of Defective Mitochondria

Award Number: R37AG047182

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2015

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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