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

沿着颅顶和颅底的脑化、负载和骨形成：颅底屈曲的机制分析

• 批准号: 2330236
• 负责人: Matthew Ravosa
• 金额: $ 50.03万
• 依托单位: Johns Hopkins University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2330236&HistoricalAwards=false
• 关键词: Encephalization; Loading; Bone; Formation; along

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.

脑化是相对脑大小的进化扩展，是灵长类动物的标志，在惊人的大脑中最著名。虽然很明显，灵长类动物的颅骨（头骨）已经进化以适应更大的脑大小，但这些修饰的机械基础尚未完全了解。在该项目中，研究人员将测试有关大脑生长在颅形态（形状）的机械作用的长期假设。使用一种新型的组织工程方法来模拟大脑扩张期间的静态拉伸负荷，将在鼠模型中检查钙化，基础和下颌骨非核骨细胞的成骨（骨产生）潜力。这项研究将促进有关颅形态的发育和细胞基础的知识，提供比较的哺乳动物数据，这些数据将为灵长类动物和人类进化的研究提供信息，并有可能为再生医学的临床研究提供依据。该项目将促进涉及STEM中代表性不足群体成员的研究和教育的跨学科方法。这将使博士后研究员，研究生和本科生以及STEM老师和学生受益，他们将在公共和地方机构中参加演讲和外展。由于其位于神经和面部颅骨的界面，哺乳动物颅底的屈曲升高被描述为越来越多的球状大脑的机械后果。然而，大多数实验证据表明，钙化骨组织在很大程度上可以缓冲机械刺激的变化。相比之下，众所周知，硬脑膜在大脑扩张过程中受拉伸力的影响，并诱导上覆的缝合骨的生长。令人惊讶的是，几乎没有证据表明，硬脑膜的神经力和促骨质信号会影响颅底和穹顶中非余骨的发展。该项目的一个主要目的是详细介绍成年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与年龄相关的变化，使用下颌骨细胞的反应作为评估钙和基础细胞的基准。研究人员将评估颅库中的骨骼形成和碱是否受到潜在硬脑膜中的促稳态信号的影响。这项研究在整合性的观点和对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头骨中骨形成的实验数据是理解重要问题的关键，包括颅拱顶厚度的适应性和灵长类动物的周围形式。颅骨机械敏感性中位点特异性变化的存在还将强调，骨形成的内在机制的差异应纳入未来在多种哺乳动物中的硬组织适应的工作，包括颅和肢体元素，具有更明显的骨反应。因此，该项目的结果将有助于生物人类学，生物学，机械生物学和病理生物学的理论和分析进步。 NSF生物人类学和生理机制和生物力学计划共同支持了这项研究。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子和更广泛影响的评估评估标准来通过评估来支持的。