| NSF Org: |
IOS Division Of Integrative Organismal Systems |
| Recipient: |
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| Initial Amendment Date: | December 21, 2023 |
| Latest Amendment Date: | November 26, 2024 |
| Award Number: | 2339761 |
| Award Instrument: | Continuing Grant |
| Program Manager: |
Anna Allen
akallen@nsf.gov (703)292-8011 IOS Division Of Integrative Organismal Systems BIO Directorate for Biological Sciences |
| Start Date: | January 15, 2024 |
| End Date: | December 31, 2028 (Estimated) |
| Total Intended Award Amount: | $1,405,000.00 |
| Total Awarded Amount to Date: | $565,000.00 |
| Funds Obligated to Date: |
FY 2025 = $275,000.00 |
| History of Investigator: |
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| Recipient Sponsored Research Office: |
360 HUNTINGTON AVE BOSTON MA US 02115-5005 (617)373-5600 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
360 HUNTINGTON AVE BOSTON MA US 02115-5005 |
| 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): | Animal Developmental Mechanism |
| Primary Program Source: |
01002526DB NSF RESEARCH & RELATED ACTIVIT 01002627DB NSF RESEARCH & RELATED ACTIVIT 01002728DB NSF RESEARCH & RELATED ACTIVIT 01002829DB NSF RESEARCH & RELATED ACTIVIT |
| 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 Faculty Early Career Development (CAREER) award will focus on elucidating the molecular mechanisms of skeletal growth. Growth plate cartilages in mammalian long bones drive skeletal growth until sexual maturity, where they fuse and are replaced by bone. This replacement of growth plate cartilage by bone is called growth plate closure. The mechanism of growth plate closure remains unclear but likely involves gradual tissue reduction and functional decline with age. Estrogen plays a vital role in growth plate closure for both sexes by converting androgens to estrogens through aromatase in growth plate cartilage. Deficiency or resistance to estrogen leads to growth plate fusion failure and ongoing height increase in adulthood. However, the exact mechanism by which estrogen regulates growth plate closure is still unknown. Understanding this mechanism may clarify species-specific skeletal differences or variations between bones from different anatomical locations. The overall objective of this proposal is to determine how skeletal growth is terminated through modulation of the growth plate stem cells depletion. This research will have eventual application to future biomechanical or pharmaceutical interventions to prevent or reverse stunted skeletal growth in children with various pathologies. The research from this project will also be integrated into an educational and outreach program based on undergraduate curriculum development via a student-led community service module to raise awareness about skeletal health in impoverished multi-racial South Boston children and promotion of undergraduate research opportunities for underrepresented minority through summer research activities and field trips. Global public outreach includes creation of a science website, showcasing faculty and student research through scientific images. These initiatives will share knowledge with the public, inspire youth of diverse backgrounds to pursue science, and foster a lasting commitment to scientific outreach.
This research proposal hypothesizes that within the growth plate, FoxA2+ long-term skeletal stem cells (LTSSC) act as both a reservoir of stem cells and a signaling hub that favors growth plate expansion rather than closure. The objectives of this study include: (1) to investigate the impact of FoxA2+ LTSSC ablation in mice, aiming to elucidate whether growth plate closure results from a reduction in available FoxA2+ stem cells capable of differentiating into PTHrP+ progeny or from the creation of a signaling environment that accelerates the depletion of PTHrP+ cells, (2) to examine the lifelong maintenance of an open growth plate in mice compared to the closure observed in rabbits (and humans) after maturity, via understanding why FoxA2+ LTSSC persist for extended periods in mice but become depleted in rabbits upon maturity, (3) to explore the role of estrogen signaling in regulating growth plate closure by influencing the exhaustion of FoxA2+ LTSSC. The anticipated impact of this CAREER project is expected to lay the groundwork for future interventions that could effectively tackle skeletal pathologies, thereby impacting potential clinical advancements. This CAREER proposal synergizes with an integrated education program, engaging students in research and outreach to the public.
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.
Please report errors in award information by writing to: awardsearch@nsf.gov.
