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Centromere identity, strength, and regulation

Award Number: R35GM130302
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: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2029

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Centromere identity, strength, and regulation - Project Summary/Abstract Chromosomes are the functional unit of inheritance and must segregate with high fidelity every time a cell divides. For eukaryotes, a common mechanism is employed, where sister chromatids are physically attached to each other and bidirectionally oriented towards poles of the microtubule-based spindle that physically move complete sets of chromosomes to the daughter cells. This bidirectionally-oriented attachment is mediated by a proteinaceous structure called the kinetochore, which forms at the microtubule/chromosome interface during mitosis. The site of kinetochore formation is defined by the centromere. Without functional centromeres, chromosomes are mis-segregated at cell division, leading to a genetic catastrophe—aneuploidy—in the daughter cells. Over the last 15+ years, the centromere has been the major focus of our attention, and altogether we have contributed to elucidating the molecular basis for centromere identity, the epigenetic pathway that propagates centromeric chromatin in perpetuity, the relationship between epigenetic and genetic information in driving centromere evolution in eukaryotes, and key steps in the quality control pathway that ensures proper chromosome segregation at cell division. Over the last ~five years, some of our most important contributions emerging from MIRA-supported projects have come through harnessing this knowledge to develop new and powerful types of human artificial chromosomes, and using standard structural biology approaches as well as solution biophysical approaches to advance our understanding of the proteins that drive chromosome inheritance at cell division. A major focus for our proposed studies will be to use cryo-electron tomography to visualize the centromere in its natural chromosomal context. In the first research area, we propose to visualize the centromere during mitosis. This work will fill a major gap in our understanding of how centromeric chromatin demarcates the site of kinetochore formation. In the second research area, we will advance our current understanding of how centromeric chromatin propagates centromere identity by visualizing this part of the chromosome at key steps through the cell cycle. Altogether, the two research areas will provide answers to vital questions related to how chromosomes are faithfully inherited through cell division.


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 = $569,538 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	7	12/16/2025	NON-COMPETING CONTINUATION	$569,538
														Subtotal = $569,538

Issue Date FY: 2025 ( Subtotal = $632,821 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	6	1/8/2025	COMPETING CONTINUATION	$632,821
														Subtotal = $632,821

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	9/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $563,113 )
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	5	3/8/2023	NON-COMPETING CONTINUATION	$563,113
														Subtotal = $563,113

Issue Date FY: 2022 ( Subtotal = $563,113 )
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	4	7/20/2022	NON-COMPETING CONTINUATION	$56,313
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	4	3/16/2022	NON-COMPETING CONTINUATION	$506,800
														Subtotal = $563,113

Issue Date FY: 2021 ( Subtotal = $563,113 )
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	3	3/9/2021	NON-COMPETING CONTINUATION	$563,113
														Subtotal = $563,113

Issue Date FY: 2020 ( Subtotal = $812,472 )
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	2	3/10/2020	NON-COMPETING CONTINUATION	$563,113
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	2	7/14/2020	SUPPLEMENT FOR EXPANSION	$249,359
														Subtotal = $812,472

Issue Date FY: 2019 ( Subtotal = $535,966 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	3/19/2019	NEW	$535,966
														Subtotal = $535,966

Grand Total All Awards = $4,240,136

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Centromere identity, strength, and regulation

Award Number: R35GM130302

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: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2029

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