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Defining the landscape and mechanisms of redox regulation of metabolism during aging

Award Number: K99AG073461
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/15/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Defining the landscape and mechanisms of redox regulation of metabolism during aging - PROJECT SUMMARY: Mammalian tissues engage in specialized physiology that is regulated through reversible modification of protein cysteine residues by reactive oxygen species (ROS). Despite the longstanding links between ROS dysregulation and aging, technological limitations have resulted in a persistent absence of information on the exact protein cysteines are modified by ROS that explain the molecular basis for this dysfunction in vivo. Using the cysteine-phospho tag (CPT) proteomics technology that I developed, I have determined that a fundamental remodeling of protein cysteine oxidation networks occurs with caloric restriction (CR) in aging. Building on this, I will determine the functional role of redox regulation of newfound protein networks that are linked to the lifespan and healthspan benefits of CR in aging. I have also extended Oximouse to diversity outbred (DO) mouse populations to recapitulate the genetic diversity of human population, in search for redox signaling targets that have high translational potential. Preliminary data from this effort has identified conserved redox signaling targets on proteins that may have critical implications in age-dependent decline of thermogenesis leading to age-related obesity. I will study metabolic redox signaling nodes underlying longevity- modifying interventions and delineate the mechanisms through which these targets are redox-regulated with age that lead to a decline in thermogenic activity. The proteomics data will provide a rich resource for the community to explore ROS and aging. The mechanistic studies will validate redox signaling nodes that can potentially be manipulated to extend lifespan and healthspan, in line with the mission of the National Institute of Aging. Objectives: (1) Defining mitochondrial cysteine oxidation mechanisms underlying the health benefits of CR. (2) Determining adipose metabolic redox signaling nodes underlying longevity-modifying interventions. (3) Investigating the mechanisms of redox control in age-related obesity. The first two objectives will be completed during the K99 phase, and the last objective will be carried out during the R00 phase. This work builds on a redox proteomics technology that I developed, which quantifies absolute cysteine redox modification stoichiometry at orders of magnitude deeper proteome coverage than previous methods. From this big data, I will mechanistically validate individual redox signaling nodes that have important roles in metabolism and longevity. I will be mentored by Drs. Chouchani and Gygi, who are experts in the fields of ROS biology, metabolism, animal physiology, and mass spectrometry (MS)-based proteomics. I will additionally learn from my collaborators/consultants, Drs. Mair, Gladyshev, Banks, Gupta, and Spiegelman, who have extensive expertise in aging, animal physiology, and metabolism. The rich scientific environment at DFCI and HMS adds fuel to my enthusiasm to establish myself as an independent investigator. My unique skillset will allow me to develop novel technologies to study the biology of aging in a “big-data” driven manner, then select targets for mechanistic validation to provide insights for future translational therapeutic development.


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 = -$106 )
2025	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	001	2	5/12/2025	NON-COMPETING CONTINUATION	-$106
2025	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	000	2	12/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = -$106

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	000	2	3/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $109,929 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	2	4/4/2023	NON-COMPETING CONTINUATION	$109,929
														Subtotal = $109,929

Issue Date FY: 2022 ( Subtotal = $109,929 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	1	5/2/2022	NEW	$109,929
														Subtotal = $109,929

Grand Total All Awards = $219,752

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Defining the landscape and mechanisms of redox regulation of metabolism during aging

Award Number: K99AG073461

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/15/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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