CAREER: Osteocyte Regulation of Bone Tissue Fracture Resistance

这个教师早期职业发展（CAREER）项目将支持旨在提高我们对骨细胞-嵌入骨组织中的应变传感细胞-如何调节骨材料特性和抗骨折性的理解的研究。治疗骨质疏松症的目标是维持骨量。然而，骨脆性不能完全由骨丢失来解释，还取决于骨基质的质量。骨细胞在调节骨基质特性方面发挥着几种重要作用，但在设计作用于这些细胞的干预措施以改善骨基质质量和由此产生的组织抗骨折性之前，必须解决几个紧迫的问题。该项目将确定骨细胞如何通过作用于其他骨细胞以及与周围骨基质的直接相互作用来强化骨组织。在这个项目中获得的知识将为开发一种新的治疗方法奠定基础，这种治疗方法的目标是通过骨细胞改善骨基质质量。这项工作的更广泛的影响是通过创建一个基于队列的计划来扩大的，该计划旨在让非传统的蒙大拿州立大学学生参与工程研究;并培训代表性不足的本科生和研究生。研究数据将被整合到一个新的高级生物力学课程以及核心工程课程。这个CAREER研究项目的首要目标是推进骨细胞对骨基质调节的基础知识。骨细胞可能以多种方式影响骨基质材料的性质以及由此产生的骨强度和断裂韧性。众所周知，骨细胞通过控制破骨细胞和成骨细胞间接决定骨基质的性质。骨细胞也可以通过去除和替换其相邻的骨基质来直接决定骨基质的性质。该项目的第一个目标是确定骨细胞的直接和间接调节活动对骨基质成分，材料性能和断裂韧性的影响。这些基质调节活动受到哺乳、负荷和卵巢切除模型的刺激。第二个目标是确定骨细胞不同基质调节活动的代谢过程。靶向和非靶向代谢组学分析的组合将揭示骨细胞在直接或间接影响骨基质的活动期间如何利用能量。从这些CAREER研究中获得的知识将为新的治疗策略奠定基础，这些策略旨在通过调节骨细胞的活动和代谢过程来改善骨基质质量。该项目由生物力学和机械生物学以及刺激竞争研究的既定计划（EPSCoR）共同资助该奖项反映了NSF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) project will support research that intends to improve our understanding of how osteocytes - strain-sensing cells embedded in bone tissue - regulate bone material properties and fracture resistance. Therapies for managing bone fragility target the maintenance of bone mass. However, bone fragility is not fully explained by bone loss but also depends on the quality of bone matrix. Osteocytes play several important roles in regulating bone matrix properties, but several urgent questions must be addressed before interventions can be designed that act on these cells to improve the bone matrix quality and the resulting tissue fracture resistance. This project will determine how osteocytes toughen bone tissue through acting on other bone cells as well as by their direct interactions with the surrounding bone matrix. Knowledge gained during this project will lay the foundation for developing a new class of therapies that target the improvement of bone matrix quality by osteocytes. The broader impacts of the work are amplified by the creation of a cohort-based program to engage nontraditional Montana State University students in engineering research; and train underrepresented, undergraduate and graduate students. Research data will be integrated into a new advanced biomechanics course as well as into core engineering courses. The overarching goal of this CAREER research project is to advance fundamental knowledge about the regulation of bone matrix by osteocytes. The osteocytes may influence bone matrix material properties and the resulting bone strength and fracture toughness in multiple ways. Osteocytes are well-known to indirectly determine bone matrix properties through their control of osteoclasts and osteoblasts. Osteocytes may also directly determine bone matrix properties by removing and replacing their neighboring bone matrix. The first objective of this project is to determine the impacts of direct and indirect osteocyte regulatory activities on bone matrix composition, material properties, and fracture toughness. These matrix-regulatory activities are stimulated by lactation, loading, and ovariectomy models. The second objective is to define the metabolic processes that underpin different matrix regulatory activities by osteocytes. A combination of targeted and untargeted metabolomic analyses will reveal how osteocytes utilize energy during activities that directly or indirectly impact bone matrix. The knowledge gained from these CAREER studies will lay the foundation for new therapeutic strategies that target the improvement of bone matrix quality through modulating the activities and metabolic processes of the osteocyte.This project is jointly funded by Biomechanics and Mechanobiology and the Established Program to Stimulate Competitive Research (EPSCoR).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.