Mechanobiological Regulation of Cortical Bone in Vertebrates

脊椎动物骨骼形态的多样性是生长和衰老过程中遗传和环境影响共同作用的结果。机械刺激是由身体活动引起的，代表着一种强大的环境影响，它调节着骨骼的生长和重塑。与“冷血”爬行动物和两栖动物相比，“温血”哺乳动物和鸟类或许能够保持相对较轻的骨骼，因为它们的骨骼细胞天生对机械负荷更敏感。然而，目前尚不清楚骨骼反应的差异是由骨细胞的差异引起的，还是由冷血和温血动物代谢率的差异引起的，还是两者的结合。该奖项将调查骨骼在不同陆生脊椎动物之间的相对适应潜力，并确定影响适应性骨形成的潜在生理、解剖和遗传调节因素。这项工作将对理解哺乳动物和鸟类之间骨骼形式的进化多样性以及与古代(化石)实例相比现代“冷血”脊椎动物骨骼结构的相对保护至关重要。将测量调节骨形成的新分子，这些分子可能在治疗骨丢失方面具有重要的生物医学应用。这项研究的结果将通过讲座、大学网站和学习模块向当地中小学生传授科学和工程概念。本研究的目的是将骨细胞诱导的骨骼合成特异性的机械敏感的Sost-Wnt/β-catenin途径的调节与人工胫骨负荷下三种陆生脊椎动物(爬行动物、鸟类和哺乳动物)的骨骼对物理刺激的骨组织反应联系起来。本文所用的多尺度基因到组织水平的方法将利用体内骨功能适应模型、体外骨组织器官培养模型、3D共聚焦显微镜和转录分析来建立对脊椎动物骨骼的分子和细胞机械生物学机制、动物代谢对生物对环境挑战的反应的影响以及影响不同脊椎动物群体结构多样性的因素的比较理解。

Diversity in skeletal form amongst vertebrate animals results from a combination of genetic and environmental influences during growth and aging. Mechanical stimuli, caused by physical activity, represent a potent environmental influence that regulates bone growth and remodeling. "Warm-blooded" mammals and birds may be able to maintain relatively light skeletons compared to "cold-blooded" reptiles and amphibians because their bone cells are inherently more responsive to mechanical loading. However, it is unclear if the differences in skeletal response are caused by differences in the bone cells, differences in the metabolic rate of "cold" and "warm" blooded animals, or a combination of both. The award will investigate the relative adaptive potential of the skeleton among different terrestrial vertebrates and determine the underlying physiological, anatomical, and genetic regulatory factors influencing adaptive bone formation. This work will be critical for understanding evolutionary diversity in skeletal form among mammals and birds and the relative conservation of skeletal structure in modern "cold-blooded" vertebrates compared to ancient (fossil) examples. Novel molecules regulating bone formation, which could have important biomedical applications for treating bone loss, will be measured. The results of this work will be presented to the public through lectures, university websites, and through learning modules to teach local elementary and junior high school students science and engineering concepts.The objective of this research is to relate regulation of the mechanosensitive Sost-Wnt/beta-catenin pathway, specific to osteocyte-induced skeletal anabolism, to the bone tissue response to physical stimuli in the skeletons of four species from three terrestrial vertebrate groups (reptiles, birds, mammals) under artificial tibial loading. The multi-scale gene- to tissue-level approach used here will utilize in vivo bone functional adaptation models, in vitro bone tissue organ culture models, 3D confocal microscopy, and transcriptomic analyses to establish a comparative understanding of molecular and cellular mechanobiological mechanisms in the vertebrate skeleton, the influence of animal metabolism on organismal response to environmental challenges, and factors influencing structural diversity across different vertebrate groups.