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Developing Deterministic Computational Models and Statistical Analysis of VEGF+PDGF Cross-Family Signaling in Adipose Tissue

Award Number: R01HL159946
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Developing Deterministic Computational Models and Statistical Analysis of VEGF+PDGF Cross-Family Signaling in Adipose Tissue - PROJECT SUMMARY/ABSTRACT The vascular endothelial growth factors (VEGFs) direct key signaling processes in obesity and at least 70 other diseases. However, focus on this signaling node alone has not achieved the promise of predictable angiogenic control. Current models are incomplete as other growth factors, besides VEGF, contribute to vascular disease progression, presenting a complexity that cannot be predictably regulated by targeting one node in this system. Therefore, there is a continuing need to account for the complexity of additional, multi-component signaling networks, a goal that can be achieved via data-driven, computational systems biology in close concert with experimental analysis of signaling and functional response. Toward this goal, we aim to examine a novel paradigm of network regulation called cross-family signaling, in which members from one growth factor family [e.g., platelet derived growth factors (PDGFs)] bind to and signal through members of another family (e.g., VEGFRs). We hypothesize that systematic examination of protein structure and downstream signaling within the cross-family paradigm via simulation, ligand-engineering, network quantification, and computational modeling can uncover novel mechanisms to control angiogenesis. We will test this hypothesis through three aims, sensitively quantifying receptor activation rates and functional responses of cross-family binding (e.g., proliferation, migration, and barrier function); predicting and measuring the structural properties of cross-family binding via molecular simulations and directed evolution; and developing validated deterministic models (mass-action kinetic modeling) of cross- family signaling and applying them to study and control the dynamics of cross-family signaling in human cell systems, in silico. We are primed to lead this new research because we are among the first to pursue this important theoretical paradigm, and we lead this cause to understand cell signaling via structure/function–based computational modeling. This work will catalyze a shift in perspective and innovation in the areas of cell signaling, systems biology, and predictive design of obesity- focused therapies.


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 = $661,427 )
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	002	4	9/20/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	001	4	8/16/2024	SUPPLEMENT FOR EXPANSION	$96,096
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	000	4	7/24/2024	NON-COMPETING CONTINUATION	$565,331
														Subtotal = $661,427

Issue Date FY: 2023 ( Subtotal = $664,682 )
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	002	3	7/12/2023	NON-COMPETING CONTINUATION	$664,682
2023	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	001	2	11/21/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$698,854
2023	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cardiovascular Diseases Research	000	1	11/21/2022	NEW	-$698,854
														Subtotal = $664,682

Issue Date FY: 2022 ( Subtotal = $777,371 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	001	2	8/23/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$777,371
2022	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	000	1	8/22/2022	NEW	$0
														Subtotal = $777,371

Issue Date FY: 2021 ( Subtotal = $698,854 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cardiovascular Diseases Research	000	1	8/27/2021	NEW	$698,854
														Subtotal = $698,854

Grand Total All Awards = $2,802,334

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Developing Deterministic Computational Models and Statistical Analysis of VEGF+PDGF Cross-Family Signaling in Adipose Tissue

Award Number: R01HL159946

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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