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

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（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，在那里它们融合并被骨骼取代。这种生长板软骨被骨替代的现象称为生长板闭合。生长板闭合的机制尚不清楚，但可能涉及随着年龄的增长逐渐减少的组织和功能下降。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期身高持续增加。然而，雌激素调节生长板关闭的确切机制仍然是未知的。了解这一机制可能会澄清物种特异性骨骼差异或来自不同解剖位置的骨骼之间的变化。本提案的总体目标是确定骨骼生长如何通过调节生长板干细胞耗竭而终止。这项研究将最终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病理的儿童骨骼生长发育不良。从这个项目的研究也将被整合到一个教育和推广计划的基础上，通过学生主导的社区服务模块，以提高对骨骼健康的认识，在贫困的多种族南波士顿儿童和促进本科研究机会，为代表性不足的少数民族通过夏季研究活动和实地考察本科课程的发展。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，激励不同背景的年轻人追求科学，并培养对科学推广的持久承诺。这项研究提案假设，在生长板内，FoxA2+长期骨骼干细胞（LTSSC）既作为干细胞的储存库，又作为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消融对小鼠的影响，旨在阐明生长板闭合是由于能够分化成PTHrP+子代的可用FoxA2+干细胞减少还是由于产生加速PTHrP+细胞耗竭的信号传导环境，（2）与在兔子中观察到的闭合相比，检查小鼠中开放生长板的终身维持（和人类）在成熟后，通过理解为什么FoxA2+ LTSSC在小鼠中持续延长的时间，但在成熟后在兔中耗尽，（3）探讨雌激素信号通过影响FoxA2+ LTSSC耗竭来调节生长板关闭的作用。该CAREER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解决骨骼病理学问题，从而影响潜在的临床进步。这个职业建议与综合教育计划协同作用，让学生参与研究和向公众推广。这个奖项反映了NSF的法定使命，并被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。