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Systems analysis of cell-to-cell variability and signaling-transcription factor motifs regulating macrophage responses to conflicting environmental cues

Award Number: R01GM123011
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Cell-to-cell variability provides a strategy by which cells can explore diverse states; little is known, however, about the regulatory motifs that stabilize particular states into cell subsets that enable diverse functions within a population. Macrophages, cells of the innate immune system, provide an ideal experimental system to study the regulation of cell subsets, because they transiently adopt polarization states (i.e., tailored sets of molecules) to meet changing functional demands in tissues. However, the polarization state adopted to perform one task is often suboptimal for–or even in opposition to–performing other tasks, raising the question of how macrophages respond to conflicting microenvironmental cues. Our recent work suggests that cell-to-cell variation in mutually inhibitory transcription factor (TF) networks increases macrophage functional diversity and enables them to meet functional demands encoded by conflicting cues. The overall objective of this proposal is to define intracellular and extracellular signaling–TF networks that regulate heterogeneous pro-inflammatory (e.g., in response to LPS+IFN-¿) vs. anti-inflammatory (e.g., in response to IL-4) macrophage subsets and ultimately coordinate a coherent functional response. Our central hypothesis is that mutually inhibitory networks establish macrophage pro- vs. anti- inflammatory subsets that are coordinated via context-dependent mechanisms. To test this hypothesis, we will integrate single-cell measurements with mathematical modeling to determine if mutual inhibition and collective sensing are important network motifs for harnessing cell-to-cell variability and organizing appropriate polarization states to meet functional demands in tissues. Achieving the proposed aims would provide an alternative way to describe the macrophage polarization spectrum in innate immunity, by conceptualizing it as a set of functional cell subsets that emerge from multiple competing network motifs. The proposed research is innovative because we will measure single-cell responses after co-stimulation with conflicting environmental cues–specifically, cues that have known mechanisms of regulatory cross talk and cell-cell communication–in order discover new regulatory mechanisms and establish new frameworks describing macrophage functional diversity. The proposed research is significant because it is expected to have broad translational potential to identify therapeutic targets that more specifically alter macrophage functional states in vivo to treat conditions characterized by dysregulation of macrophage functions.


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 = $300,751 )
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Biomedical Research and Research Training	000	7	1/9/2024	NON-COMPETING CONTINUATION	$300,751
														Subtotal = $300,751

Issue Date FY: 2023 ( Subtotal = $334,564 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Biomedical Research and Research Training	001	6	2/10/2023	NON-COMPETING CONTINUATION	$33,456
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Biomedical Research and Research Training	000	6	1/20/2023	NON-COMPETING CONTINUATION	$301,108
														Subtotal = $334,564

Issue Date FY: 2022 ( Subtotal = $334,944 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Biomedical Research and Research Training	000	5	4/11/2022	COMPETING CONTINUATION	$334,944
2022	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Biomedical Research and Research Training	001	4	8/2/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $334,944

Issue Date FY: 2020 ( Subtotal = $297,768 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Biomedical Research and Research Training	000	4	1/30/2020	NON-COMPETING CONTINUATION	$267,991
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Biomedical Research and Research Training	001	4	3/6/2020	NON-COMPETING CONTINUATION	$29,777
														Subtotal = $297,768

Issue Date FY: 2019 ( Subtotal = $298,831 )
2019	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Biomedical Research and Research Training	000	3	2/20/2019	NON-COMPETING CONTINUATION	$298,831
														Subtotal = $298,831

Issue Date FY: 2018 ( Subtotal = $294,650 )
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Biomedical Research and Research Training	001	2	5/28/2018	NON-COMPETING CONTINUATION	$29,465
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Biomedical Research and Research Training	000	2	1/19/2018	NON-COMPETING CONTINUATION	$265,185
														Subtotal = $294,650

Issue Date FY: 2017 ( Subtotal = $290,425 )
2017	2017	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	NEW HAVEN	USA	Biomedical Research and Research Training	000	1	2/27/2017	NEW	$290,425
														Subtotal = $290,425

Grand Total All Awards = $2,151,933

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Systems analysis of cell-to-cell variability and signaling-transcription factor motifs regulating macrophage responses to conflicting environmental cues

Award Number: R01GM123011

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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