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Decoding the logic of cellular signaling through the integration of dynamic, single-cell and multiplexed methods

Award Number: R35GM133404
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: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Decoding the logic of cellular signaling through the integration of dynamic, single-cell and multiplexed methods - PROJECT SUMMARY – Responses of cells to signaling perturbations exhibit complex dynamics that vary across diverse cell types or even genetically identical cells exposed to uniform conditions. Heterogeneity arises partly because of the cells’ ability to process the signaling input in the context of their states controlled by their epigenome, a regulatory network involving transcription factors and chromatin architecture which, although contains heritable information about gene expression programs, remains plastic. Such plasticity enables cells to transition from one phenotype to another and exhibit fractional responses to perturbations. Despite this knowledge, what remains largely unknown is: (i) the nature of these dynamically fluctuating phenotypically consequential cell states, and how they determine the context for signal transduction, (ii) mechanisms that control the diversity of these states, their multi-stability or plasticity, and variation across cell types, and (iii) mechanisms by which information embedded in these states is integrated with that from signaling input to elicit state-specific decisions. Our proposed research is significant because it addresses these key gaps in our understanding through the study of AP-1 transcription factor network, which we recently showed to serve as a key node in linking MAPK signal transduction to diverse patterns of cell state plasticity. Individual cells can adopt a variety of AP-1 states regulated by a combination of competitive homo- and heterodimeric interactions between individual AP-1 proteins, whose levels and stability are also subject to transcriptional (auto)regulation and posttranslational modification by MAP kinases. We have shown that the diversity of recurrent AP-1 states and their single-cell frequencies vary across differentiation states and predict their phenotypic plasticity prior to and following MAPK perturbations. We propose to determine how combinatorial patterns of AP-1 network shape cell state heterogeneity and plasticity via analyzing a panel of model-guided, AP-1 perturbed, isogenic cells to decompose the impact of diverse AP-1 dimers on chromatin features, networks of transcriptional coregulators, the resulting gene expression programs, and single-cell responses to MAPK perturbations. We will build the first generation of experimentally validated models of AP-1 regulated expression system based on their dimerization-controlled, co-regulated, competitive interactions, and use them to reveal network features underlying the diversity of multi-stable AP-1 states in different cell populations. Side-by-side virtual and wet-lab single-cell experiments will uncover pharmacologically tractable targets to modulate population heterogeneity via stabilizing or destabilizing certain AP-1 states. We will use multiplexed single-cell imaging in combination with multivariate modeling to determine how the trajectory of adaptive responses to MAPK perturbations and their phenotypic outcomes are determined through the integration of treatment-induced changes in the AP-1 network. Understanding these fundamental mechanisms will lead to novel strategies to manipulate cell state plasticity and new opportunities to improve precision medicine via guiding cells toward the desired phenotypes.


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 = $390,973 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	004	7	6/20/2025	NON-COMPETING CONTINUATION	$390,973
2025	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	6	11/18/2024	COMPETING CONTINUATION	$0
2025	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	002	6	4/1/2025	COMPETING CONTINUATION	$5,572
2025	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	001	5	4/1/2025	NON-COMPETING CONTINUATION	-$5,417
2025	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	003	4	4/1/2025	SUPPLEMENT FOR EXPANSION	-$155
														Subtotal = $390,973

Issue Date FY: 2024 ( Subtotal = $390,973 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	001	6	8/5/2024	COMPETING CONTINUATION	$390,973
2024	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	5	7/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $390,973

Issue Date FY: 2023 ( Subtotal = $376,696 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	001	5	7/7/2023	NON-COMPETING CONTINUATION	$366,198
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	4	5/1/2023	SUPPLEMENT FOR EXPANSION	$10,498
														Subtotal = $376,696

Issue Date FY: 2022 ( Subtotal = $504,238 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	4	7/18/2022	NON-COMPETING CONTINUATION	$355,193
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	001	4	7/22/2022	SUPPLEMENT FOR EXPANSION	$149,045
														Subtotal = $504,238

Issue Date FY: 2021 ( Subtotal = $318,437 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	002	3	6/30/2021	NON-COMPETING CONTINUATION	$318,437
2021	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	001	2	1/21/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$300,000
2021	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	1	1/21/2021	NEW	-$300,000
														Subtotal = $318,437

Issue Date FY: 2020 ( Subtotal = $325,098 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	001	2	7/6/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$325,098
2020	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	1	7/3/2020	NEW	$0
														Subtotal = $325,098

Issue Date FY: 2019 ( Subtotal = $362,206 )
2019	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	1	8/7/2019	NEW	$362,206
														Subtotal = $362,206

Grand Total All Awards = $2,668,621

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Decoding the logic of cellular signaling through the integration of dynamic, single-cell and multiplexed methods

Award Number: R35GM133404

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: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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