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Dissecting signaling in vivo via precise control and visualization of protein activity

Award Number: R35GM122596
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: 04/01/2017
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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View Award Description

Dissecting signaling in vivo via precise control and visualization of protein activity - Abstract An ongoing revolution in microscopy has revealed previously inaccessible aspects of signaling. These include organization of signaling proteins on dynamic cytoskeletal elements, subtle but important variations in activation kinetics, and information encoded in the oscillation frequencies of signaling circuits. We will explore these regulatory mechanisms by developing novel approaches to visualize and control protein activity, and by using them together in the same cell. Novel image analysis methods and computational modeling applied to multiplexed imaging data will reveal causal connections between signaling events, including those dependent on nested feedback loops. We will pursue new methods to produce biosensors bright enough to study the conformational changes of individual molecules in living cells. On podosomes and adhesion complexes, where important dynamic structures are organized on a scale below the diffraction limit, we will use these new methods to examine the opening of stretch-activated binding sites in real time. Proteins will be controlled with light or small molecules using engineered domains inserted away from the active site, where they can allosterically control activity without perturbing normal interactions. We will study three model systems that are well suited to extract basic principles re the spatio-temporal regulation of signaling: 1) In 'frustrated phagocytosis' macrophages attempt to engulf micropatterned circles. The phagocytic apparatus they build around the circles has precise, reproducible geometry, which will enable us to use quantitative image analysis and simultaneous protein control/visualization to develop mathematical models. 2) We will study how cancer cells move on aligned collagen superhighways to find blood vessels. There we will ask how cells use localized signaling to sense and respond to anisotropic mechanical stresses. 3) Finally, cell protrusion/retraction will be used to examine the integration of chemical gradients, mechanical force, and cytoskeletal dynamics. We hope that the behavior of these model systems will reveal ubiquitous signaling mechanisms, and that the new tools can help others explore diverse questions in cell biology.


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: 2026 ( Subtotal = $810,270 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	10	4/6/2026	NON-COMPETING CONTINUATION	$810,270
														Subtotal = $810,270

Issue Date FY: 2025 ( Subtotal = $810,270 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	001	9	4/7/2025	NON-COMPETING CONTINUATION	$810,270
2025	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	8	11/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $810,270

Issue Date FY: 2024 ( Subtotal = $810,270 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	001	8	7/15/2024	NON-COMPETING CONTINUATION	$81,027
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	8	3/11/2024	NON-COMPETING CONTINUATION	$729,243
														Subtotal = $810,270

Issue Date FY: 2023 ( Subtotal = $810,270 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	7	3/10/2023	NON-COMPETING CONTINUATION	$810,270
2023	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	002	6	3/14/2023	COMPETING CONTINUATION	$1,048
2023	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	001	5	3/14/2023	NON-COMPETING CONTINUATION	-$1,048
														Subtotal = $810,270

Issue Date FY: 2022 ( Subtotal = $810,270 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	001	6	5/24/2022	COMPETING CONTINUATION	$810,270
2022	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	5	5/16/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $810,270

Issue Date FY: 2021 ( Subtotal = $789,940 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	5	4/16/2021	NON-COMPETING CONTINUATION	$789,940
														Subtotal = $789,940

Issue Date FY: 2020 ( Subtotal = $789,940 )
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	4	4/2/2020	NON-COMPETING CONTINUATION	$789,940
														Subtotal = $789,940

Issue Date FY: 2019 ( Subtotal = $789,940 )
2019	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	3	4/1/2019	NON-COMPETING CONTINUATION	$789,940
														Subtotal = $789,940

Issue Date FY: 2018 ( Subtotal = $719,260 )
2018	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	002	2	9/18/2018	SUPPLEMENT FOR EXPANSION	$97,778
2018	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	2	3/29/2018	NON-COMPETING CONTINUATION	$559,333
2018	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	001	2	5/21/2018	NON-COMPETING CONTINUATION	$62,149
														Subtotal = $719,260

Issue Date FY: 2017 ( Subtotal = $282,964 )
2017	2017	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	1	3/15/2017	NEW	$282,964
														Subtotal = $282,964

Grand Total All Awards = $7,423,394

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Dissecting signaling in vivo via precise control and visualization of protein activity

Award Number: R35GM122596

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: 04/01/2017

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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