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的综合结果。由身体活动引起的机械刺激代表了调节骨生长和重塑的有力环境影响。与“冷血”爬行动物和两栖动物相比，“温血”哺乳动物和鸟类可能能够保持相对较轻的骨骼，因为它们的骨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，“冷血”和“温血”动物代谢率的差异，还是两者的组合引起的。该奖项将调查不同陆生脊椎动物骨骼的相对适应潜力，并确定影响适应性骨形成的潜在生理，解剖和遗传调控因素。这项工作对于理解哺乳动物和鸟类骨骼形式的进化多样性以及与古代（化石）例子相比现代“冷血”脊椎动物骨骼结构的相对保护至关重要。新的分子调节骨形成，这可能有重要的生物医学应用治疗骨丢失，将被测量。这项工作的结果将通过讲座、大学网站和学习模块向公众展示，以教授当地小学和初中生科学和工程概念。本研究的目的是将骨细胞诱导的骨骼强直特异性的机械敏感性Sost-Wnt/β-catenin通路的调节与骨细胞诱导的骨骼强直相关，研究了三个陆生脊椎动物类群（爬行动物、鸟类、哺乳动物）四种动物骨骼在人工胫骨载荷作用下对物理刺激的骨组织反应。这里使用的多尺度基因-组织水平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组学分析来建立对脊椎动物骨骼中分子和细胞机械生物学机制的比较理解，动物代谢对生物体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。

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.