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Mechanisms of Signaling on Membrane Surfaces

Award Number: R35GM144346
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: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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View Award Description

Mechanisms of Signaling on Membrane Surfaces - SUMMARY At the leading edge of a polarized macrophage, a membrane-based chemotaxis pathway directs cell mi- gration up attractant gradients to sites of infection, inflammation, or tissue damage. Upon arrival, a phagocyto- sis pathway controls the formation and internalization of a phagosome in which the pathogens or damaged tis- sue are engulfed and destroyed. Both the chemotaxis and phagocytosis pathways are regulated by PI3K lipid kinases that serve as regulatory hubs by integrating Ca2+, receptor, G protein, and other input signals while phosphorylating substrate lipids to produce output lipid signals. The potent lipid signals, in turn, activate multi- ple downstream protein kinases. In chemotaxis, the lipid signal controls actin and membrane remodeling to drive the leading edge up the attractant gradient. In phagocytosis, the lipid signal controls processing of the phagosome including the production of reactive oxygen species (ROS) to inactivate pathogens. Closely related PI3K pathways regulate other cell processes, notably including cell growth. When dysregulated, PI3K path- ways trigger or exacerbate a wide array of human diseases ranging from cancer and developmental disorders to defects in innate immunity, inflammation or autoimmunity. The two classes of PI3K lipid kinases targeted by this research program are Class 1 PI3-Kinases (PI3K1) that generate the signaling lipid PIP3 at the leading edge membrane of polarized macrophages, and Class 3 PI3-Kinases (PI3K3, specifically PI3K3 Complex II) that produce PI3P on the surface of the phagosome. The proposed research seeks to understand the regulation of both pathways by addressing fundamental, broad questions including: (i) How do PI3K1 and PI3K3 regulatory hubs integrate multiple inputs from Ca2+ channels, receptors, G proteins and other effectors, and do these inputs combine in additive, synergistic, or opposing fashions? (ii) How do the resulting PIP3 and PI3P output lipids activate downstream protein kinases, including some of the most important master kinases in the cell? (iii) How do drugs, potential therapeutics, and disease- linked mutations inhibit or superactivate key components and reaction steps to generate pathway perturbation or dysregulation? To answer these and other questions, the PI's laboratory has developed a unique, two-pronged approach combining innovative, in vitro single molecule methods with live cell imaging studies. The in vitro studies utilize single molecule TIRF to elucidate signaling mechanisms in a subsection of the pathway, or signaling module, that is reconstituted on a supported lipid bilayer under near physiological conditions. The live cell studies em- ploy fluorescent sensors and cell imaging to test key predictions of the in vitro mechanistic model for relevance in the cellular context. The PI has a strong track record and continues to play leadership roles in his research field, as well as the university and scientific communities. Overall, this research program is well positioned to continue generating fundamental advances with significant impacts on signaling biology and medicine.


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 = $379,632 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	5	12/23/2025	NON-COMPETING CONTINUATION	$341,669
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80303	BOULDER	USA	Biomedical Research and Research Training	001	5	3/16/2026	NON-COMPETING CONTINUATION	$37,963
														Subtotal = $379,632

Issue Date FY: 2025 ( Subtotal = $379,887 )
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	002	4	8/6/2025	NON-COMPETING CONTINUATION	$37,988
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	4	12/23/2024	NON-COMPETING CONTINUATION	$341,899
2025	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	3	11/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $379,887

Issue Date FY: 2024 ( Subtotal = $380,138 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	3	12/15/2023	NON-COMPETING CONTINUATION	$342,124
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	3	6/18/2024	NON-COMPETING CONTINUATION	$38,014
														Subtotal = $380,138

Issue Date FY: 2023 ( Subtotal = $380,382 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	2	12/9/2022	NON-COMPETING CONTINUATION	$342,345
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	2	4/5/2023	NON-COMPETING CONTINUATION	$38,037
														Subtotal = $380,382

Issue Date FY: 2022 ( Subtotal = $438,119 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	1	12/17/2021	NEW	$438,119
														Subtotal = $438,119

Grand Total All Awards = $1,958,158

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Mechanisms of Signaling on Membrane Surfaces

Award Number: R35GM144346

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: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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