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Structure and Pharmacologic Modulation of the Mitotic Chromosome's Central Axis

Award Number: DP5OD033431
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/13/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Structure and Pharmacologic Modulation of the Mitotic Chromosome's Central Axis - Project Summary Mitotic chromosome formation is essential for the dissemination of genetic information in eukaryotes. The conversion of dispersed interphase chromatin into the iconic, X-shaped metaphase chromosome involves three principal events: the formation of a central axis (the chromosomal “scaffold”), lengthwise contraction, and condensation. Plausible theories have been advanced to explain the latter two events, with contraction occurring through the extrusion of chromatin loops and condensation occurring through a volume phase transition of the chromosomal material. In contrast, little is known about the formation of the mitotic scaffold, and its very existence has been the source of considerable controversy. Direct evidence for the scaffold's existence has recently come from the observation of a central filament in native mitotic chromosomes subjected to controlled expansion ex vivo. This filament could be liberated, intact, from its chromosomal confines by careful nucleolysis, providing a basis for further study. This proposal aims to elucidate basic principles of the mitotic chromosome scaffold, including its molecular composition (Aim 1), its three-dimensional architecture (Aim 2), and its interactions with the chromatin enveloping it (Aims 1 and 2). The information obtained will provide a global view of the core of the mitotic chromosome, explaining how its components assemble into a structure of mesoscopic proportions and how this structure organizes the genome in a manner ensuring its faithful and efficient distribution. The acquired knowledge will enable more detailed investigations into the mechanisms governing scaffold assembly and disassembly and the nature of its interactions with other cellular components (e.g., chromatin, kinetochores). This proposal also seeks to develop chemical modulators of scaffold assembly (Aim 3). As the scaffold and its constituents are increasingly understood to play important roles in human health and disease, such tools will not only enable further research on the scaffold but will also allow for its pharmacological manipulation in clinical contexts. Dysregulation of scaffold components such as the condensins, for instance, has been implicated in a growing number of malignancies, where they contribute to a particular form of genome instability known as chromosome instability. Genome instability is a key factor in the evolution of cancer cells, facilitating their escape from immune clearance and their acquisition of therapeutic resistance. By suppressing a pathway leading to chromosome instability, modulators of condensins (and other scaffold components) may act to limit the evolutionary potential of cancer cells.


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 = $787,321 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Trans-NIH Research Support	001	4	8/6/2025	EXTENSION WITH OR WITHOUT FUNDS	$787,321
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Trans-NIH Research Support	000	3	8/6/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $787,321

Issue Date FY: 2024 ( Subtotal = $393,661 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Trans-NIH Research Support	000	3	8/12/2024	NON-COMPETING CONTINUATION	$393,661
														Subtotal = $393,661

Issue Date FY: 2023 ( Subtotal = $393,661 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Trans-NIH Research Support	000	2	8/31/2023	NON-COMPETING CONTINUATION	$393,661
														Subtotal = $393,661

Issue Date FY: 2022 ( Subtotal = $393,661 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Trans-NIH Research Support	000	1	9/13/2022	NEW	$393,661
														Subtotal = $393,661

Grand Total All Awards = $1,968,304

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Structure and Pharmacologic Modulation of the Mitotic Chromosome's Central Axis

Award Number: DP5OD033431

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/13/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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