CAREER: Understanding how hierarchical organization of growth plate stem cells controls skeletal growth

职业：了解生长板干细胞的分层组织如何控制骨骼生长

• 批准号: 2339761
• 负责人: Andreia Ionescu
• 金额: $ 140.5万
• 依托单位: Northeastern University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-15 至 2028-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2339761&HistoricalAwards=false
• 关键词: CAREER; Understanding; how; hierarchical; organization; CAREER; Understanding; how; hierarchical; organization

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.

这个教师早期职业发展（职业）奖将重点阐明骨骼生长的分子机制。哺乳动物长骨的生长板软骨驱动骨骼生长，直到性成熟为止，在那里它们融合并被骨骼取代。通过骨骼代替生长板软骨称为生长板闭合。生长板闭合的机制尚不清楚，但可能涉及随着年龄的增长的逐渐减少和功能下降。通过将雄激素转化为雌激素，通过生长板软骨中的芳香酶转化为雌激素，雌激素在生长板闭合中起着至关重要的作用。缺乏或对雌激素的耐药性会导致生长板融合失败和成年期的持续增加。但是，雌激素调节生长板闭合的确切机制仍然未知。了解这种机制可能会阐明物种特异性的骨骼差异或来自不同解剖位置的骨骼之间的变化。该提案的总体目的是确定如何通过调节生长板干细胞耗尽来终止骨骼生长。这项研究最终将应用于未来的生物力学或药物干预措施，以预防或逆转各种病理儿童的骨骼生长。该项目的研究还将通过学生为主导的社区服务模块基于本科课程开发的教育和外展计划，以提高对贫困的多种族的南波士顿儿童的认识，并促进通过夏季研究活动和实地考察的少数群体促进少数群体的本科生研究机会。全球公共宣传包括创建科学网站，通过科学图像展示教师和学生研究。这些举措将与公众分享知识，激发各种背景的年轻人追求科学，并促进对科学宣传的持久承诺。这项研究提案假设，在增长板中，FOXA2+长期骨骼干细胞（LTSSC）在生长板中充当干细胞的储层，又是信号群的储层，而不是有利于增长板的增长。 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成熟后，在兔（和人类）中观察到的闭合是通过理解为什么FOXA2+ LTSSC在小鼠中长期长时间持续存在，但在成熟时会在兔子中耗尽，（3）探索雌激素信号传导在调节生长板闭合中的作用，通过影响FOXA2+ LTSSC的精疲力尽。预计该职业项目的预期影响将为未来的干预措施奠定基础，这些干预措施可能有效地应对骨骼病理，从而影响潜在的临床进步。该职业建议与综合教育计划协同，使学生参与研究并与公众进行宣传。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛的影响评估标准通过评估来获得支持的。