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Chemical Biology Approaches for Studying Circadian Rhythms

Award Number: R35GM143016
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: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Chemical Biology Approaches for Studying Circadian Rhythms - Project Summary/Abstract Circadian clocks are time-tracking systems that allow organisms to adapt to the time of day, and drive many cellular functions. Their alteration can lead to various diseases, including cancer, heart disease, and metabolic disorders. In this work, we propose development of a chemical biology toolbox, consisting of both imaging and protein-targeting platforms to facilitate studies of circadian rhythms at the molecular level that have otherwise not been possible. The core clock is comprised of a transcriptional-translational feedback loop with multiple protein components, including paralogs. Disparities have been observed between promoter activity and protein translation, among responses of core clock components to stimuli, and compensatory mechanisms resulting from knock-down and knock-out strategies. To address these gaps and facilitate additional studies of the molecular clock, we will use chemical biology-based strategies to: 1.) generate orthogonal chemiluminescent scaffolds to track promoter activity and protein translation of multiple circadian genes in a parallel, high-content manner; and 2.) develop small molecule and protein-based tools to directly target circadian proteins and their interactions. For studies of the molecular clock, it is essential to track circadian rhythms and target core clock proteins in a dynamic and selective manner. Firefly luciferase-based reporters have been used to assess promoter activity of individual circadian genes, and most protein-based studies involve cells derived from a single luminescent mouse model. We will use orthogonal chemiluminescent probes (Nano-lanterns) to develop a multi-signal platform to simultaneously track and associate promoter activity and protein translation relationships among multiple genes. Perturbation of circadian proteins is also essential for understanding mechanisms, including paralog roles. Currently, there are few options outside of genetic approaches, which can result in unilateral changes and activation of network compensation mechanisms. Molecular tools offer the ability to directly target the functional components of the clock – proteins, and/or their interactions. While small molecules present an attractive approach, relatively few exist that directly target core clock proteins. Hence, we propose to generate new agents for interrogating the circadian clock system: we will repurpose validated clock protein-binding small molecules by synthetically converting them into protein degraders (PROTACs), and use yeast surface-display to identify nanobodies that bind circadian proteins and prevent specific interactions. Together, these approaches present a powerful means to understand the mechanisms of the circadian clock, and can be used in a variety of models and in studies of diseases, including to uncover new therapeutic targets.


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 = $381,815 )
2025	2025	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	5	5/13/2025	NON-COMPETING CONTINUATION	$381,815
														Subtotal = $381,815

Issue Date FY: 2024 ( Subtotal = $382,707 )
2024	2024	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	4	5/2/2024	NON-COMPETING CONTINUATION	$382,707
														Subtotal = $382,707

Issue Date FY: 2023 ( Subtotal = $383,600 )
2023	2023	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	3	5/8/2023	NON-COMPETING CONTINUATION	$383,600
														Subtotal = $383,600

Issue Date FY: 2022 ( Subtotal = $349,548 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	2	5/17/2022	NON-COMPETING CONTINUATION	$349,548
														Subtotal = $349,548

Issue Date FY: 2021 ( Subtotal = $354,510 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	1	6/24/2021	NEW	$354,510
														Subtotal = $354,510

Grand Total All Awards = $1,852,180

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Chemical Biology Approaches for Studying Circadian Rhythms

Award Number: R35GM143016

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: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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