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

该学院早期职业发展（Career）奖将专注于阐明骨骼生长的分子机制。哺乳动物长骨中的生长板软骨驱动骨骼生长，直到性成熟，它们融合并被骨骼取代。这种用骨代替生长板软骨的过程称为生长板闭合。生长板闭合的机制尚不清楚，但可能与随着年龄增长而逐渐减少的组织和功能下降有关。雌激素通过生长板软骨中的芳香化酶将雄激素转化为雌激素，在两性生长板闭合中起着至关重要的作用。雌激素缺乏或抵抗导致生长板融合失败和成年后持续的身高增加。然而，雌激素调节生长板闭合的确切机制尚不清楚。了解这一机制可以澄清物种特异性骨骼差异或不同解剖位置骨骼之间的差异。本提案的总体目标是确定骨骼生长是如何通过调节生长板干细胞枯竭而终止的。这项研究将最终应用于未来的生物力学或药物干预，以预防或逆转患有各种疾病的儿童骨骼发育迟缓。该项目的研究还将通过学生主导的社区服务模块整合到基于本科课程开发的教育和推广计划中，以提高贫困的多种族南波士顿儿童对骨骼健康的认识，并通过夏季研究活动和实地考察促进代表性不足的少数民族的本科研究机会。全球公共推广包括建立一个科学网站，通过科学图片展示教师和学生的研究。这些举措将与公众分享知识，激励不同背景的青年追求科学，并促进对科学推广的持久承诺。本研究假设，在生长板内，FoxA2+长期骨骼干细胞（LTSSC）既是干细胞的储存库，也是有利于生长板扩张而不是关闭的信号中枢。本研究的目的包括：(1)研究FoxA2+ LTSSC消融对小鼠的影响，旨在阐明生长板关闭是由于能够分化为PTHrP+后代的FoxA2+干细胞减少，还是由于创造了一个加速PTHrP+细胞消耗的信号环境；(2)与兔（和人）成熟后观察到的关闭相比，研究小鼠开放生长板的终身维持。通过理解FoxA2+ LTSSC在小鼠体内持续较长时间而在家兔成熟后耗尽的原因，(3)探讨雌激素信号通过影响FoxA2+ LTSSC的耗尽在调节生长板闭合中的作用。该CAREER项目的预期影响有望为未来有效解决骨骼疾病的干预奠定基础，从而影响潜在的临床进展。这个职业建议与综合教育计划协同作用，让学生参与研究并向公众宣传。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.