Encephalization, Loading and Bone Formation along the Cranial Vault and Base: Mechanistic Analysis of Basicranial Flexion

脑化，即相对大脑大小的进化扩张，是灵长类动物的一个标志，最显著的是人类惊人的大大脑。虽然很明显，灵长类动物的头盖骨已经进化到可以适应更大的大脑，但这些变化的机制基础还没有完全理解。在这个项目中，研究人员将测试长期以来关于大脑生长对颅骨形态（形状）的机械作用的假设。利用一种新颖的组织工程方法来模拟大脑扩张过程中的静态拉伸载荷，将在小鼠模型中检查颅骨、颅底和下颌非缝合线骨细胞的成骨（产骨）潜力。这项研究将推进关于颅骨形态学的发育和细胞基础的知识，提供哺乳动物的比较数据，这将为灵长类动物和人类进化的研究提供信息，并可能为再生医学的临床研究提供信息。该项目将促进涉及STEM中代表性不足群体成员的跨学科研究和教育方法。它将使博士后、研究生和本科生以及STEM教师和学生受益，他们都将参加公共和地方机构的演讲和推广活动。由于其位于神经和面部头骨的交界面，哺乳动物颅底的高屈曲被描述为大脑日益球形的机械后果。然而，大多数实验证据表明，颅骨骨组织在很大程度上缓冲了机械刺激的变化。相反，硬脑膜在脑扩张过程中受到拉伸力的影响，并诱导上覆缝合骨的生长。令人惊讶的是，几乎没有证据表明硬脑膜的神经力和促成骨信号在多大程度上影响颅底和拱顶非缝合骨的发育。该项目的一个主要目标是详细描述生长颅骨中结缔组织成骨潜能和机械敏感性的部位特异性和年龄相关变化，使用下颌骨细胞的反应作为基线来评估颅骨和颅底细胞。研究人员将评估颅顶和颅底的骨形成是否受到底层硬脑膜促骨信号的影响。这项研究在其综合视角和组织工程方法的新颖使用方面具有变革性。关于硬脑膜如何调节颅骨骨形成的实验数据是理解一些重要问题的关键，包括灵长类动物颅穹窿厚度和绕眶形状的适应性。颅下颌骨机械敏感性的位点特异性变异也强调了骨形成内在机制的变异应该被纳入到未来对不同哺乳动物硬组织适应性的研究中，包括具有更明显骨反应的颅和肢体成分。因此，项目成果将有助于生物人类学、有机体生物学、机械生物学和病理生物学的理论和分析进步。本研究由美国国家科学基金会生物人类学和生理机制与生物力学项目共同支持。该奖项反映了美国国家科学基金会的法定使命，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。

Encephalization, the evolutionary expansion of relative brain size, is a hallmark of Primates and most notable in the amazingly large human brain. While it is evident that primate crania (skulls) have evolved to accommodate larger brain sizes, the mechanistic underpinnings of these modifications are not fully understood. In this project, the investigators will test long-held assumptions about the mechanical role of brain growth on cranial morphology (shape). Using a novel tissue engineering approach to simulate static tensile loads during brain expansion, the osteogenic (bone producing) potential of calvarial, basicranial and mandibular non-sutural bone cells will be examined in a murine model. The research will advance knowledge about the developmental and cellular underpinnings of cranial morphology, provide comparative mammalian data that will inform studies in primate and hominin evolution, and potentially inform clinical research in regenerative medicine. The project will foster interdisciplinary approaches to research and education involving members of under-represented groups in STEM. It will benefit a postdoctoral fellow, graduate students and undergraduates as well as STEM teachers and students, all of whom will participate in presentations and outreach at public and local institutions. Due to its location at the interface of neural and facial skulls, elevated flexion of the mammalian cranial base is depicted as the mechanical consequence of an increasingly globular brain. However, most experimental evidence indicates that calvarial bony tissues are largely buffered against variation in mechanical stimuli. In contrast, the dura mater is known to be affected by tensile forces during brain expansion and induces growth of overlying sutural bone. Surprisingly, there is little evidence about the extent to which neural forces and pro-osteogenic signaling by the dura affect the development of non-sutural bone in the cranial base and vault. A major goal of this project is to detail site-specific and age-related variation in the osteogenic potential and mechanosensitivity of connective tissues in the growing skull, using the responses of mandibular bone cells as a baseline to evaluate calvarial and basicranial cells. The investigators will assess if bone formation in the cranial vault and base is affected by pro-osteogenic signaling in the underlying dura mater. This research is transformative in its integrative perspective and novel use of tissue engineering methods. Experimental data on how the dura mater modulates bone formation in the skull is key for understanding important questions, including the adaptive nature of cranial vault thickness and circumorbital form in primates. The presence of site-specific variation in craniomandibular mechanosensitivity would also emphasize that variation in intrinsic mechanisms of bone formation should be incorporated into future work on hard-tissue adaptations in diverse mammals, including cranial and limb elements with more marked bony responses. The project outcomes will therefore contribute to both theoretical and analytical advances in biological anthropology, organismal biology, mechanobiology and pathobiology. This research is jointly supported by the NSF Biological Anthropology and the Physiological Mechanisms and Biomechanics programs.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.