| NSF Org: |
MCB Division of Molecular and Cellular Biosciences |
| Recipient: |
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| Initial Amendment Date: | January 4, 2022 |
| Latest Amendment Date: | August 26, 2024 |
| Award Number: | 2143869 |
| Award Instrument: | Continuing Grant |
| Program Manager: |
Richard Cyr
rcyr@nsf.gov (703)292-8440 MCB Division of Molecular and Cellular Biosciences BIO Directorate for Biological Sciences |
| Start Date: | January 1, 2022 |
| End Date: | December 31, 2026 (Estimated) |
| Total Intended Award Amount: | $1,112,526.00 |
| Total Awarded Amount to Date: | $891,873.00 |
| Funds Obligated to Date: |
FY 2023 = $12,000.00 FY 2024 = $451,230.00 |
| History of Investigator: |
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| Recipient Sponsored Research Office: |
100 INSTITUTE RD WORCESTER MA US 01609-2280 (508)831-5000 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
100 INSTITUTE RD WORCESTER MA US 01609-2247 |
| Primary Place of
Performance Congressional District: |
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| Unique Entity Identifier (UEI): |
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| Parent UEI: |
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| NSF Program(s): |
Cellular Dynamics and Function, Cross-BIO Activities |
| Primary Program Source: |
01002425DB NSF RESEARCH & RELATED ACTIVIT 01002526DB NSF RESEARCH & RELATED ACTIVIT 01002627DB NSF RESEARCH & RELATED ACTIVIT 010V2122DB R&RA ARP Act DEFC V |
| Program Reference Code(s): |
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| Program Element Code(s): |
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| Award Agency Code: | 4900 |
| Fund Agency Code: | 4900 |
| Assistance Listing Number(s): | 47.074 |
ABSTRACT
This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117- 2).
Cell division is an essential process required for cellular proliferation and organismal growth. Dramatic defects in cell division can result in non-viable daughter cells and compromise organismal growth. More subtle defects during cell division promote changes in the genome that contribute to cellular evolution. The cell?s genetic material is organized into discrete structures known as chromosomes. When a cell divides the chromosomes are sorted equally into the two new daughter cells by a molecular machine called the mitotic spindle. The interactions between the spindle and chromosomes are governed, in part, by modifications made to the protein molecules that organize the genetic material. However, the distinct modifications that are critical for accurate chromosome sorting, and the regulatory processes that control when these modifications are placed or removed, are not completely understood. This project will investigate the key modifications that are necessary for the formation of connections between chromosomes and the cell division machinery. The investigator will use cell and molecular approaches to modify individual regulators and corresponding modifications. Using high resolution microscopy, this research will experimentally test the relevance of each modification in the cell division process, leading to a better understanding of both the regulation of chromosomes and, more generally, the fundamental process of cell division. The Broader Impacts of this work include the intrinsic merit of the research itself as all eukaryotic cells likely utilize the processes to be studied. Additional activities include efforts to increase the diversity in STEM, involvement of high school students, undergraduates, and graduate students in the research itself. Efforts to improve scientific literacy are proposed. American Rescue Plan funding provides support for this investigator at a critical stage in her career.
Mitotic chromosome segregation is an essential process required for cellular proliferation and organismal growth. During mitosis, chromosomes are segregated into two daughter cells by a microtubule based structure known as the mitotic spindle. Microtubules attach to chromosomes via the kinetochore, a proteinaceous structure built upon the centromere. The centromere is defined epigenetically by the deposition of CENPA, a Histone H3 variant. Together with post-translational modifications of histone tails in centromeric chromatin, CENPA recruits the core proteins necessary for kinetochore formation. Flanking the centromere are regions of constitutive heterochromatin, termed the pericentromere. While epigenetic modulation of centromeric and pericentromeric heterochromatin has been implicated in the regulation of chromosome segregation, the molecular and mechanistic basis by which epigenetic and molecular constituents of pericentromeric heterochromatin impact kinetochore structure and function remain unclear. This project will utilize molecular, cellular, and imaging approaches to mechanistically define the role of epigenetic modulation of pericentromeric heterochromatin on the regulation of mitotic error correction and chromosome segregation. By identifying key epigenetic modulators of mitotic fidelity and defining the underlying mechanism by which mitosis is compromised when the corresponding epigenetic modifications are disrupted, this project will advance both our understanding of the biological significance of the pericentromeric heterochromatin and more broadly our understanding of the fundamental process of cell division.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
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