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Non-transcriptional regulation of circadian physiology

Award Number: R01DK124068
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/11/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Non-transcriptional regulation of circadian physiology - PROJECT SUMMARY Robust daily biological rhythms are key hallmarks of animal healthspan and are strongly regulated by circadian clocks. These cell-autonomous molecular timers enable animals to adapt to predictable daily changes in their environment. Clock-controlled outputs are all-encompassing and clock disruption is associated with a wide range of pathologies and chronic diseases. In the natural world, environmental signals, e.g. light and temperature, enable animal circadian clocks to control timing of food intake. Nutrient influx can therefore provide metabolic signals to reinforce environmental signals, promoting synchrony in cellular physiology to balance metabolism and energy use. Efforts to understand the underpinnings of circadian clocks and their control over daily biological rhythms have long focused on regulation at the transcriptional level, as core oscillator proteins are transcription factors that govern rhythmic expression of genes involved in diverse cellular processes. However, more recent studies have uncovered complementary non- transcriptional mechanisms, including protein post-translational modifications (PTMs), that are critical for maintaining robust daily rhythms. The overall goal of this project is to advance our understanding of the role of nutrient-dependent PTMs in mediating metabolic regulation of time- of-day-specific protein functions to orchestrate daily biological rhythms. We will use the diurnal Drosophila model to test the central hypothesis that the timing and lipid content of metabolic input from food intake and cellular metabolism regulate rhythmic S-palmitoylation of cellular proteins, and S-palmitoylation is necessary for maintenance of robust daily biological rhythms. S- palmitoylation is the only reversible lipid PTM; it is the attachment of palmitate, a saturated fatty acid, to cysteines. S-palmitoylation targets a wide range of proteins from transcription factors to membrane receptors, and is known to alter their stability, activity, localization, and protein-protein interactions. The specific aims of this project are to investigate the mechanisms by which timing of metabolic signals and clock-regulated lipid metabolism regulate S-palmitoylation rhythms and how these rhythms are impacted by increased lipid content in food (Aim 1); to identify proteins that exhibit daily rhythms in S-palmitoylation (Aim 2); and to determine if S-palmitoylation regulates daily biology rhythms (Aim 3). This project will advance our long-term goal to integrate post-translational regulatory pathways and obtain a comprehensive understanding of how daily biological rhythms are regulated by diet, nutrition, and timing of metabolic input. This project will have broad significance as misregulation in S-palmitoylation has been linked to a plethora of human diseases including cancer, metabolic, neurological, and immunological disorders.


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 = $482,072 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	2/26/2025	NON-COMPETING CONTINUATION	$433,865
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	7/9/2025	NON-COMPETING CONTINUATION	$48,207
														Subtotal = $482,072

Issue Date FY: 2024 ( Subtotal = $497,223 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	5	9/9/2024	COMPETING CONTINUATION	$94,464
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/23/2024	COMPETING CONTINUATION	$497,223
2024	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	8/13/2024	NON-COMPETING CONTINUATION	-$8,894
2024	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	8/13/2024	SUPPLEMENT FOR EXPANSION	-$85,570
														Subtotal = $497,223

Issue Date FY: 2022 ( Subtotal = $463,115 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	8/26/2022	SUPPLEMENT FOR EXPANSION	$85,570
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/1/2022	NON-COMPETING CONTINUATION	$377,545
														Subtotal = $463,115

Issue Date FY: 2021 ( Subtotal = $464,474 )
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	8/17/2021	SUPPLEMENT FOR EXPANSION	$85,570
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	8/18/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/4/2021	NON-COMPETING CONTINUATION	$378,904
														Subtotal = $464,474

Issue Date FY: 2020 ( Subtotal = $380,140 )
2020	2020	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/24/2020	NON-COMPETING CONTINUATION	$380,140
														Subtotal = $380,140

Issue Date FY: 2019 ( Subtotal = $381,264 )
2019	2019	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/12/2019	NEW	$381,264
														Subtotal = $381,264

Grand Total All Awards = $2,668,288

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Non-transcriptional regulation of circadian physiology

Award Number: R01DK124068

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/11/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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