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

脑化是大脑相对大小的进化扩张，是灵长类动物的标志，在令人惊讶的大人脑中最显着。虽然很明显灵长类动物的颅骨已经进化到可以容纳更大的大脑尺寸，但这些变化的机械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。使用一种新的组织工程方法来模拟脑扩张过程中的静态拉伸负荷，将在小鼠模型中检查颅骨、颅底和下颌骨非缝合骨细胞的成骨（骨生成）潜力。该研究将推进有关颅骨形态的发育和细胞基础的知识，提供比较哺乳动物数据，为灵长类动物和人类进化研究提供信息，并可能为再生医学的临床研究提供信息。该项目将促进跨学科的研究和教育方法，涉及STEM中代表性不足的群体的成员。它将使博士后研究员，研究生和本科生以及STEM教师和学生受益，所有人都将参加公共和地方机构的演讲和推广活动。由于其位置在神经和面部头骨的界面，哺乳动物颅底的弯曲度升高被描述为日益球形的大脑的机械后果。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。相比之下，已知硬脑膜在脑扩张期间受到张力的影响，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穹隆的非缝合骨的发育。该项目的一个主要目标是详细说明生长中颅骨中结缔组织的成骨潜力和机械敏感性的位点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。研究者将评估颅顶和颅底的骨形成是否受到下层硬脑膜中促成骨信号的影响。这项研究在其综合视角和组织工程方法的新用途方面具有变革性。关于硬脑膜如何调节颅骨中骨形成的实验数据是理解重要问题的关键，包括灵长类动物颅穹窿厚度和眶周形状的适应性。颅下颌机械敏感性的位点特异性变化的存在也将强调，骨形成的内在机制的变化应纳入未来的工作，在不同的哺乳动物的硬组织适应，包括颅骨和肢体元素更显着的骨反应。因此，该项目的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展。这项研究由NSF生物人类学和生理机制和生物力学项目共同支持。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。

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.