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Regulation of cell, tissue, and nucleus function by mechanical properties of biopolymer networks

Award Number: R35GM136259
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: 04/15/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2030

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Regulation of cell, tissue, and nucleus function by mechanical properties of biopolymer networks - Project Summary Changes in the physical properties of tissues are often associated with disease, not simply as consequences of pathology but as drivers of it. Cells build structures that are strong enough to resist the mechanical stresses that are generated by external forces such as gravity and impact, as well as those that emerge from the same molecular structures and cellular assemblies that evolved to generate biological movement and force. This MIRA renewal application combines two physical studies related to cell and tissue function. One study continues to be focused on the mechanical properties of purified biopolymer networks derived from the cytoskeleton and the extracellular matrix, intact cells, and whole tissues, and expands on previous work that defines of the elastic properties of these materials to also consider their dissipative features. Mechanical energy dissipation in biological material can arise from the viscoelasticity of the protein networks, poroelasticity from water/cytosol flow through the network pores, or random motor-driven movements of network strands. We have built new instruments to measure poroelastic relaxation and visualize fluid flow at the micron scale and collaborate with theorists to provide models beyond the classic Darcy theory that are needed for these non-linear systems with anomalous Poisson's ratios. The second related set of studies is focused on the cell's nucleus. This is a new direction initiated in the current MIRA period showing that the nucleus is highly deformable by small but long- lived stresses, because most of the work of deformation is dissipated rather than elastically stored. The dissipation depends on ATP hydrolysis and the function of a specific nuclear motor: the BRG1 ATPase of a chromatin remodeling complex. We plan to characterize the functions of this motor complex in molecular detail and determine if the motor itself responds to force, as do some cytoskeletal motors. We will extend our current studies of nuclei in karyoplasts to cell types other than fibroblasts and focus on explaining how the stiffness of the nucleus is altered when cells are cultured under different mechanical conditions. We will continue work with theorists to explain the nonlinear elastic response of semi-flexible polymer networks and determine how they are altered by particles within the network mesh (e.g. ribosomes or vesicles in the actin network, protein condensates in the nucleus, cells within the ECM of tissue) and thereby show how these physical models help explain nucleus, cell, and tissue mechanics. We also continue studies to show how important viscoelastic properties of the substrate, especially dissipation, are to cell phenotypes and to develop new materials by which to study them.


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: 2026 ( Subtotal = $670,509 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	6	2/11/2026	COMPETING CONTINUATION	$670,509
2026	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	2/9/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $670,509

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	11/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $626,644 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	3/12/2024	NON-COMPETING CONTINUATION	$563,979
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	5	7/23/2024	NON-COMPETING CONTINUATION	$62,665
														Subtotal = $626,644

Issue Date FY: 2023 ( Subtotal = $681,895 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	4	7/11/2023	SUPPLEMENT FOR EXPANSION	$55,251
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	4	4/5/2023	NON-COMPETING CONTINUATION	$626,644
														Subtotal = $681,895

Issue Date FY: 2022 ( Subtotal = $539,437 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	3	6/23/2022	NON-COMPETING CONTINUATION	$53,946
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	3	3/28/2022	NON-COMPETING CONTINUATION	$485,491
														Subtotal = $539,437

Issue Date FY: 2021 ( Subtotal = $364,739 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	2	3/30/2021	NON-COMPETING CONTINUATION	$364,739
														Subtotal = $364,739

Issue Date FY: 2020 ( Subtotal = $363,897 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	4/15/2020	NEW	$363,897
														Subtotal = $363,897

Grand Total All Awards = $3,247,121

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Regulation of cell, tissue, and nucleus function by mechanical properties of biopolymer networks

Award Number: R35GM136259

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: 04/15/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2030

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