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Mechanical homeostasis of nuclear and mitotic machinery across the cell cycle

Award Number: R35GM138083
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: 09/01/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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Mechanical homeostasis of nuclear and mitotic machinery across the cell cycle - Project Summary/Abstract Cellular functions require adaptive coordination of mechanical outputs with biochemical regulation, yet how mechanical forces serve as regulatory signals remains a fundamental knowledge gap in cell biology. During the previous funding period, as an early stage investigator, I launched my laboratory, developing innovative techniques that combine laser ablation with quantitative modeling to probe spindle forces in mammalian cells and in the fission yeast S. pombe. We uncovered fundamental principles of how mitotic machinery integrates mechanical input and responds to physical damage. Building on these achievements, we will now investigate how force serves as a critical signal during nuclear division, focusing on two essential processes: chromosome segregation by the mitotic spindle and maintenance of nuclear envelope integrity. In Program 1, we will extend our work on spindle microtubule bundles to determine how forces generated by and exerted on bundles regulate their dynamics and mechanics throughout mitosis. We show preliminary data demonstrating that the microtubule-associated protein ase1 not only crosslinks microtubules but also stabilizes them against depolymerization. Using a combination of laser ablation to sever bundles, optical trapping to directly apply forces, and targeted molecular perturbations to ase1 and other candidate molecules, we will elucidate the mechanisms by which microtubule bundles sense and respond to mechanical inputs. We will compare findings across fission yeast, mammalian cells, and in vitro reconstituted systems, thus identifying conserved principles of force-responsive regulation in spindle function. In Program 2, we will investigate how the nuclear envelope adapts across the cell cycle to maintain its mechanical integrity. We show preliminary data demonstrating the discovery that the S. pombe nuclear envelope possesses cell cycle-dependent repair capabilities, with mitotic nuclei repairing more efficiently than interphase nuclei. These data suggest a sweet spot of envelope tension for maintaining integrity and facilitating repair. By applying mechanical perturbations to nuclear envelopes in biological systems with distinctive mitotic strategies - S. pombe (closed mitosis), S. japonicus (semi-open mitosis), and mammalian cells (open mitosis) - we will identify both conserved and system-specific mechanisms of nuclear envelope mechanical regulation. This comparative approach will reveal how organisms solve the challenge of maintaining nuclear integrity during division, regardless of their mitotic strategy. Overall, using state-of-the-art mechanical perturbations and experimental systems spanning mammalian cells, fission yeasts, and in vitro reconstitution, my laboratory will identify core principles of how cells transduce mechanical forces into biochemical signals during nuclear division. Our findings will establish new paradigms for understanding how cells sense and respond to mechanical forces, with implications for diseases involving chromosome missegregation and nuclear envelope dysfunction.


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 = $410,577 )
2026	2026	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Biomedical Research and Research Training	001	6	5/14/2026	COMPETING CONTINUATION	$410,577
2026	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Biomedical Research and Research Training	000	5	5/5/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $410,577

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Biomedical Research and Research Training	000	5	7/23/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $366,035 )
2024	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Biomedical Research and Research Training	000	5	8/13/2024	NON-COMPETING CONTINUATION	$366,035
														Subtotal = $366,035

Issue Date FY: 2023 ( Subtotal = $366,035 )
2023	2023	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Biomedical Research and Research Training	000	4	8/28/2023	NON-COMPETING CONTINUATION	$366,035
														Subtotal = $366,035

Issue Date FY: 2022 ( Subtotal = $366,035 )
2022	2022	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Biomedical Research and Research Training	000	3	8/31/2022	NON-COMPETING CONTINUATION	$366,035
														Subtotal = $366,035

Issue Date FY: 2021 ( Subtotal = $366,035 )
2021	2021	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Biomedical Research and Research Training	000	2	8/27/2021	NON-COMPETING CONTINUATION	$366,035
														Subtotal = $366,035

Issue Date FY: 2020 ( Subtotal = $366,035 )
2020	2020	NORTH CAROLINA STATE UNIVERSITY	2701 SULLIVAN DR STE 240	RALEIGH	NC	27695	WAKE	USA	Biomedical Research and Research Training	000	1	7/30/2020	NEW	$366,035
														Subtotal = $366,035

Grand Total All Awards = $2,240,752

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Mechanical homeostasis of nuclear and mitotic machinery across the cell cycle

Award Number: R35GM138083

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: 09/01/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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