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Molecular and metabolic influences on the activation of monocytes and macrophages at single-cell resolution

Award Number: R35GM148218
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: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Molecular and metabolic influences on the activation of monocytes and macrophages at single-cell resolution - Project Summary/Abstract Monocytes and macrophages function in diverse processes, from homeostatic maintenance to immune responses and tissue regeneration. These functions are coordinated with and strongly influenced by cellular metabolism via mechanisms that are increasingly studied and characterized in populations of macrophages. However, such studies mask the cell-to-cell variation which is an inherent property of macrophage diversity. Indeed, single-cell transcriptomics data have demonstrated that macrophage polarization is better described by continuous gradients rather than by discrete states amenable to isolation and population analysis. Yet, transcriptional measurements are insufficient to characterize the metabolic and protein networks that shape monocyte and macrophage diversity. To understand how these networks control macrophage polarization and functions, we propose to directly quantify proteins and regulatory signals (such as localization of key regulators, e.g., NF-κB) in primary human monocytes and macrophages responding to physiologically relevant metabolic environments. Furthermore, we will extend this single-cell analysis to the responses of these cells to pathogen-associated molecular patterns and damage-associated molecular patterns. These data will enable us to identify likely regulatory networks driving monocyte and macrophage responses to metabolic states and molecular patterns. Subsequently, we will test these networks via pharmacological and genetic perturbations. We are uniquely positioned to perform this research since we recently pioneered methods for quantifying thousands of proteins across many single cells. Furthermore, we have the required expertise in analyzing metabolic systems (including aerobic glycolysis, which is frequently associated with macrophage activation) and developing new algorithms for data analysis. This project will advance our understanding of macrophage immunometabolism and polarization, will introduce methods for more sensitive and accurate single-cell analysis, and will provide a proof-of-principle demonstration of the possibility to identify protein-mediated molecular mechanisms at single-cell resolution. We strongly believe that attaining these goals will have a transformative impact on biomedical research and will inform new and better therapeutic strategies.


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 = $393,298 )
2025	2025	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	3	5/19/2025	NON-COMPETING CONTINUATION	$393,298
2025	2024	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	2	11/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $393,298

Issue Date FY: 2024 ( Subtotal = $411,604 )
2024	2024	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	2	9/6/2024	SUPPLEMENT FOR EXPANSION	$132,485
2024	2024	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	2	6/26/2024	NON-COMPETING CONTINUATION	$279,119
														Subtotal = $411,604

Issue Date FY: 2023 ( Subtotal = $287,115 )
2023	2023	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	1	5/11/2023	NEW	$287,115
														Subtotal = $287,115

Grand Total All Awards = $1,092,017

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Molecular and metabolic influences on the activation of monocytes and macrophages at single-cell resolution

Award Number: R35GM148218

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: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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