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

这项教师早期职业发展奖将集中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推动骨骼生长，直到性成熟，在性成熟期间，它们融合并被骨骼取代。这种生长板软骨被骨取代的过程称为生长板闭合。生长板关闭的机制尚不清楚，但可能涉及随着年龄的增长逐渐减少组织和功能衰退。雌激素通过生长板软骨中的芳香酶将雄激素转化为雌激素，在生长板关闭过程中起着至关重要的作用。雌激素缺乏或抵抗会导致生长板融合失败和成年后持续的身高增加。然而，雌激素调节生长板关闭的确切机制仍不清楚。了解这一机制可能会澄清不同解剖位置的骨骼之间的物种特异性骨骼差异或差异。这项建议的总体目标是确定如何通过调节生长板干细胞耗竭来终止骨骼生长。这项研究最终将应用于未来的生物力学或药物干预，以防止或逆转患有各种疾病的儿童的骨骼发育迟缓。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外联计划中，以提高对贫困的多种族南波士顿儿童骨骼健康的认识，并通过暑期研究活动和实地考察，促进代表不足的少数族裔的本科研究机会。全球公众宣传包括创建一个科学网站，通过科学图像展示教职员工和学生的研究。这些举措将与公众分享知识，激励不同背景的年轻人追求科学，并培养对科学探索的持久承诺。这项研究提案假设，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枢纽。本研究的目的包括：(1)研究FOXA2+LTSSC对小鼠生长板关闭的影响，旨在阐明生长板关闭是由于可分化为PTHrP+后代的FOXA2+干细胞减少还是由于信号环境的建立加速了PTHrP+细胞的枯竭；(2)通过了解为什么FOXA2+LTSSC在小鼠体内持续较长时间，但在兔(和人)成熟后会枯竭，来研究小鼠开放生长板的终生维持与兔(和人)的关闭相比。(3)通过影响FOXA2+LTSSC的耗竭，探讨雌激素信号在调节生长板关闭中的作用。这一职业项目的预期影响预计将为未来的干预措施奠定基础，这些干预措施可以有效地处理骨骼病理，从而影响潜在的临床进步。这项职业计划与综合教育计划相结合，让学生参与研究和面向公众的推广。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.