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Understanding the control mechanisms of 3D cell migration from new dimensions

Award Number: R35GM138179
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: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Understanding the control mechanisms of 3D cell migration from new dimensions - Cell migration in 3D tissue space is of fundamental importance for human biology. However, predicting and programming 3D cell motility remain as major challenges despite of a firm picture of the molecular machineries involved. To fill the knowledge gap between the overwhelming subcellular details such as protein-protein interactions, and the fascinating dynamic patterns exhibited by different cell types in tissue spaces, I will focus on the mesoscale cellular dynamics, namely the migration mode transitions of cells in 3D extracellular matrix (ECM). My lab has developed deep-learning based image postprocessing to track the migration modes of cells. We also developed techniques to manipulate and measure the micromechanics of ECM at cellular scale. Based on these preliminary results, I will systematically study the intrinsic and extrinsic control mechanisms of 3D cell migration mode transitions in collagen ECM. The results will pave the way for my long-term goals to understand the organizing principle that lead molecules to life, and to program cell motility for applications in tissue engineering and cancer treatment. To this end, I will dedicate my lab to the following research thrusts. Thrust 1 aims to determine how cell migration mode transitions are regulated by external cues, as well as intrinsic states of cells during the Epithelial-Mesenchymal Transition (EMT). I will test three hypotheses that elucidate the roles of ECM micromechanical stiffness, anisotropy, plasticity, synergy of mechanical and chemical guidance, as well as EMT stage in modulating the cell migration mode transitions. I will employ sophisticated ECM engineering and characterization techniques developed in my lab. I will also use genetically engineered cells whose EMT transcription factors are fluorescent labeled and can be specifically activated. Completion of thrust 1 will establish 3D cell migration as a hidden Markov process where the mesoscale dynamics, namely the migration mode transitions, provides a unifying framework to explain diverse dynamic patterns of 3D cell migration observed in vivo. Thrust 2 aims to devise strategies to program cell migration via nonstationary mechanical cues. In subproject 1, I will employ techniques developed in my lab to control 3D contact guidance cues in space and in real time. By measuring the migration mode transitions under step-increasing contact guidance, I will obtain the energy barriers that separate different modes. Then under periodic mechanical stimuli I will measure and computationally model the nonequilibrium mode transition flux, a statistical physics quantity that inform the efficiency and energy dissipation of cell motility responses. These mesoscale quantities shed light to the underlying molecular organizing principles. In subproject 2 I will develop collagen ECM which exhibits digital response to stresses using DNA-grafted nanoparticles as crosslinkers. I will design the DNA sequence to control the yield strength of crosslinkers, thereby programing cell migration mode both for single cell and for collective organoid migration. Completion of thrust 2 will expands the design space of engineered ECM, laying a foundation for the mechanical programing of 3D cell motility.


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 = $352,506 )
2024	2024	OREGON STATE UNIVERSITY	1500 SW JEFFERSON AVE	CORVALLIS	OR	97331	BENTON	USA	Biomedical Research and Research Training	000	5	5/22/2024	NON-COMPETING CONTINUATION	$352,506
														Subtotal = $352,506

Issue Date FY: 2023 ( Subtotal = $352,506 )
2023	2023	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Biomedical Research and Research Training	000	4	4/25/2023	NON-COMPETING CONTINUATION	$352,506
														Subtotal = $352,506

Issue Date FY: 2022 ( Subtotal = $519,539 )
2022	2022	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Biomedical Research and Research Training	000	3	5/25/2022	NON-COMPETING CONTINUATION	$352,506
2022	2022	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Biomedical Research and Research Training	001	3	7/15/2022	SUPPLEMENT FOR EXPANSION	$167,033
														Subtotal = $519,539

Issue Date FY: 2021 ( Subtotal = $352,506 )
2021	2021	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Biomedical Research and Research Training	000	2	4/22/2021	NON-COMPETING CONTINUATION	$352,506
														Subtotal = $352,506

Issue Date FY: 2020 ( Subtotal = $352,506 )
2020	2020	OREGON STATE UNIVERSITY	1500 SW JEFFERSON ST	CORVALLIS	OR	97331	BENTON	USA	Biomedical Research and Research Training	000	1	6/18/2020	NEW	$352,506
														Subtotal = $352,506

Grand Total All Awards = $1,929,563

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Understanding the control mechanisms of 3D cell migration from new dimensions

Award Number: R35GM138179

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: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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