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Unraveling the molecular connections that link circadian rhythms and lipid metabolism

Award Number: R01GM141374
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: 03/10/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Unraveling the molecular connections that link circadian rhythms and lipid metabolism - PROJECT SUMMARY Misalignments and disruption of the circadian clock lead to metabolic and physiological dysfunctions. The clock regulates metabolism whereas metabolic activities feedback to influence circadian rhythms, and this interplay between the clock and metabolism coordinates physiology. However, one major knowledge gap is the limited understanding of the mechanism by which metabolism affects clock function. The goal of the proposed research is to elucidate the molecular mechanism by which the circadian clock and lipid metabolism are interconnected through the interaction and reciprocal regulation between lipid mediators and major clock regulators using the model organism Arabidopsis thaliana. The feasibility of the proposed research is supported by recent findings that the central glycerolipid metabolic intermediate, phosphatidic acid (PA), directly binds to the clock transcription factor LHY (LATE ELONGATED HYPOCOTYL), manipulations of PA-metabolizing activities alter clock outputs, and disruptions of the clock perturb lipid accumulation in Arabidopsis. The hypothesis is that the PA-LHY interaction functions as a cellular conduit to integrate the circadian clock with lipid metabolism and mediate lipid production and organismal responses to changing environments. To test the hypothesis, Aim 1 will characterize PA interaction with the clock regulators by determining the lipid binding specificity to LHY, the amino acid residues involved in PA binding, and the intracellular location of the PA-LHY interaction using subcellular-specific PA biosensors and mass spectrometry. Aim 2 will address how altered PA metabolism entrains the circadian clock and mediates stress responses by identifying genes/enzymes responsible for producing PA species that alter clock function. Through quantifying the effect of cellular PA changes on the expression of genes involved in clock regulation, these data will be used to model how cellular PA changes lead to alterations in circadian rhythms and clock outputs. Aim 3 will determine how the circadian clock affects lipid metabolism by using clock mutants to assess how misalignments between internal circadian rhythms and the external environment affect lipid metabolism and accumulation. In addition, clock-targeted genes in lipid metabolism will be identified and tested for roles in the circadian regulation of lipid accumulation. The proposed studies will reveal new regulatory mechanisms for both the circadian clock and lipid metabolism and will advance the current understanding of the interplay between these two pathways. The results are relevant to human health because PA is a lipid mediator involved in mammalian clock regulation and various pathological processes, and the basic molecular mechanism of the clock is conserved between plants and humans. Therefore, the impact of the proposed work is to advance foundational knowledge for the molecular interconnection between lipid metabolism and the clock in eukaryotes, and the information has the potential for future strategies for understanding and mitigating metabolic and physiological dysfunctions associated with clock disruptions.


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 = $0 )
2025	2024	UNIVERSITY OF MISSOURI SYSTEM	1 UNIVERSITY BLVD	SAINT LOUIS	MO	63121	SAINT LOUIS	USA	Biomedical Research and Research Training	000	4	6/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $295,695 )
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	1 UNIVERSITY BLVD	SAINT LOUIS	MO	63121	SAINT LOUIS	USA	Biomedical Research and Research Training	000	4	1/17/2024	NON-COMPETING CONTINUATION	$266,126
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	1 UNIVERSITY BLVD	SAINT LOUIS	MO	63121	SAINT LOUIS	USA	Biomedical Research and Research Training	001	4	7/11/2024	NON-COMPETING CONTINUATION	$29,569
														Subtotal = $295,695

Issue Date FY: 2023 ( Subtotal = $382,729 )
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	ONE UNIVERSITY BLVD	SAINT LOUIS	MO	63121	SAINT LOUIS	USA	Biomedical Research and Research Training	001	3	5/15/2023	SUPPLEMENT FOR EXPANSION	$13,249
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	ONE UNIVERSITY BLVD	SAINT LOUIS	MO	63121	SAINT LOUIS	USA	Biomedical Research and Research Training	002	3	6/12/2023	SUPPLEMENT FOR EXPANSION	$72,479
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	ONE UNIVERSITY BLVD	SAINT LOUIS	MO	63121	SAINT LOUIS	USA	Biomedical Research and Research Training	000	3	2/16/2023	NON-COMPETING CONTINUATION	$297,001
														Subtotal = $382,729

Issue Date FY: 2022 ( Subtotal = $298,764 )
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	ONE UNIVERSITY BLVD	SAINT LOUIS	MO	63121	SAINT LOUIS	USA	Biomedical Research and Research Training	001	2	8/3/2022	NON-COMPETING CONTINUATION	$29,877
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	ONE UNIVERSITY BLVD	SAINT LOUIS	MO	63121	SAINT LOUIS	USA	Biomedical Research and Research Training	000	2	2/1/2022	NON-COMPETING CONTINUATION	$268,887
														Subtotal = $298,764

Issue Date FY: 2021 ( Subtotal = $356,544 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	ONE UNIVERSITY BLVD	SAINT LOUIS	MO	63121	SAINT LOUIS	USA	Biomedical Research and Research Training	001	1	9/14/2021	SUPPLEMENT FOR EXPANSION	$38,605
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	ONE UNIVERSITY BLVD	SAINT LOUIS	MO	63121	SAINT LOUIS	USA	Biomedical Research and Research Training	000	1	3/10/2021	NEW	$317,939
														Subtotal = $356,544

Grand Total All Awards = $1,333,732

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Unraveling the molecular connections that link circadian rhythms and lipid metabolism

Award Number: R01GM141374

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: 03/10/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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