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The Linchpin that Joins the Circadian Oscillator to Clock Output

Award Number: R01GM107521
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: 05/15/2014
PERIOD OF PERFORMANCE END DATE: 04/30/2023

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The Linchpin that Joins the Circadian Oscillator to Clock Output - PROJECT SUMMARY/ABSTRACT ! Numerous life forms including bacteria, fungi, plants, and animals involuntarily regulate their metabolism, physiology, and behavior in anticipation of sunrise and sunset. These circadian rhythms arise from endogenous molecular timekeeping systems, called circadian clocks, which generate waves of assembly and disassembly of clock components. Unknown are the temporal and causal relationships between these transitory events, and how they are important to clock function. The objective of the LiWang lab is to elucidate the dynamic mechanism by which these waves are produced by and transmitted from the circadian oscillator, through clock-output pathways, to transcription factor-DNA binding rhythms. The approach is to carry out real-time measurements in vitro on the cyanobacterial circadian clock, reconstituted in its entirety (six proteins and DNA) outside the milieu of live cells. Despite the availability of a near-complete set of high-resolution structures of cyanobacterial clock protein complexes (manuscript under review at Science, submitted on 06/04/16), the dynamic mechanism of this system remains obscure. Thus, the LiWang lab is conducting real-time experiments on reconstituted cyanobacterial circadian clock reactions to unravel the dynamic timekeeping mechanism of this system. In aim 1, the LiWang lab will elucidate the temporal and causal relationships between transitory interaction events at the molecular level, using real-time nuclear magnetic resonance spectroscopy (NMR). Time signals will be followed as they propagate from the KaiABC oscillator, through the antagonistic output pathways, mediated by SasA and CikA proteins, to generate circadian rhythms of RpaA-DNA binding. In aim 2, the temporally regulated signal transmission network involving specific residues across KaiC (the heart of the clock) will be mapped, from sites of phosphorylation to the KaiA-binding sites (daytime) and KaiB- and SasA-binding sites (nighttime), using real-time NMR. Preliminary data on both aims demonstrate feasibility. This proposal is innovative, because for the first time, it will be possible to observe the rippling of time signals across the lengths of circadian clock proteins and their transmission from one clock component to the next, cycle after circadian cycle, in real time. This proposal is significant, because resolving temporal interactions within and between clock components will reveal the dynamic machinery that generates and propagates waves of clock signals, and thereby provide insights into biological timekeeping that are unobtainable from static structures.


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: 2024 ( Subtotal = -$25,368 )
2024	2021	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	000	8	2/13/2024	NON-COMPETING CONTINUATION	-$25,368
														Subtotal = -$25,368

Issue Date FY: 2022 ( Subtotal = $6,059 )
2022	2017	UNIVERSITY OF CALIFORNIA MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	000	4	9/26/2022	NON-COMPETING CONTINUATION	$6,059
														Subtotal = $6,059

Issue Date FY: 2021 ( Subtotal = $326,357 )
2021	2021	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95344	MERCED	USA	Biomedical Research and Research Training	000	8	4/23/2021	NON-COMPETING CONTINUATION	$326,357
														Subtotal = $326,357

Issue Date FY: 2020 ( Subtotal = $576,143 )
2020	2020	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95344	MERCED	USA	Biomedical Research and Research Training	000	7	4/29/2020	NON-COMPETING CONTINUATION	$327,688
2020	2020	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95344	MERCED	USA	Biomedical Research and Research Training	001	7	8/17/2020	SUPPLEMENT FOR EXPANSION	$248,455
														Subtotal = $576,143

Issue Date FY: 2019 ( Subtotal = $328,898 )
2019	2019	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95344	MERCED	USA	Biomedical Research and Research Training	000	6	5/20/2019	NON-COMPETING CONTINUATION	$328,898
														Subtotal = $328,898

Issue Date FY: 2018 ( Subtotal = $453,497 )
2018	2018	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95344	MERCED	USA	Biomedical Research and Research Training	001	5	3/8/2018	COMPETING CONTINUATION	$329,998
2018	2018	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95344	MERCED	USA	Biomedical Research and Research Training	002	5	9/1/2018	SUPPLEMENT FOR EXPANSION	$123,499
2018	2018	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95344	MERCED	USA	Biomedical Research and Research Training	004	5	9/16/2018	COMPETING CONTINUATION	$6,059
2018	2017	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95344	MERCED	USA	Biomedical Research and Research Training	003	4	9/16/2018	NON-COMPETING CONTINUATION	-$6,059
2018	2017	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95344	MERCED	USA	Biomedical Research and Research Training	000	4	3/5/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $453,497

Issue Date FY: 2017 ( Subtotal = $280,265 )
2017	2017	UNIVERSITY OF CALIFORNIA MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	001	4	8/9/2017	NON-COMPETING CONTINUATION	$28,027
2017	2017	UNIVERSITY OF CALIFORNIA MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	000	4	5/1/2017	NON-COMPETING CONTINUATION	$252,238
														Subtotal = $280,265

Issue Date FY: 2016 ( Subtotal = $280,264 )
2016	2016	UNIVERSITY OF CALIFORNIA, MERCED	5200 NORTH LAKE ROAD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	000	3	4/29/2016	NON-COMPETING CONTINUATION	$280,264
														Subtotal = $280,264

Issue Date FY: 2015 ( Subtotal = $280,265 )
2015	2015	UNIVERSITY OF CALIFORNIA, MERCED	5200 NORTH LAKE ROAD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	000	2	5/18/2015	NON-COMPETING CONTINUATION	$280,265
														Subtotal = $280,265

Issue Date FY: 2014 ( Subtotal = $294,014 )
2014	2014	UNIVERSITY OF CALIFORNIA, MERCED	5200 NORTH LAKE ROAD	MERCED	CA	95343	MERCED	USA	Biomedical Research and Research Training	000	1	5/7/2014	NEW	$294,014
														Subtotal = $294,014

Grand Total All Awards = $2,800,394

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The Linchpin that Joins the Circadian Oscillator to Clock Output

Award Number: R01GM107521

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: 05/15/2014

PERIOD OF PERFORMANCE END DATE: 04/30/2023

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