CAREER: A New Science of Skeletal and Physiological Systems: using integrated approaches to elucidate mineralized tissue properties and behavior

非技术摘要：该职业计划旨在整合材料科学，生物学和化学，以阐明磷酸氢盐对骨溶解的作用，骨是一种重要的原型和普遍存在的生物材料。该程序应用多尺度多模型技术来了解磷酸氢盐如何影响骨结构，组成和溶解过程中的功能。骨骼提供结构支持，但它也提供缓冲离子，如碳酸盐和磷酸氢盐，这些离子是调节环境酸度变化所必需的。尽管对酸/碱调节至关重要，但骨矿物质溶解的机制仍不清楚。这项研究计划将建立必要的科学基础，以操纵和生产复杂的缓冲材料，可用于环境修复以及酸/碱疾病的新治疗，如酸中毒，改善数百万人的生活质量。此外，研究者的自我效能教育计划运用了自我效能的心理学概念，将研究与教育结合起来。通过促进进入STEM环境，通过角色建模增加参与，并通过指导来支持学生，研究人员将最大限度地提高通过自我效能建立信心的因素，并促进STEM的参与。STEM访问将涉及本科生，研究生，医学和牙科学生在研究员实验室的积极研究经验。“生物材料”和“舞蹈物理”课程将进一步吸引这些学生参加STEM教学活动。女工程师协会将提供一个平台，在K-12和本科水平的角色建模。支架式指导计划将为学生提供成功应对未来职业挑战所需的支持。技术摘要：骨是一种非常复杂的生物材料，具有生物，化学和机械作用。它提供了明显的结构支持，但也调节重要的生化和生理过程，包括酸/碱平衡。骨的陶瓷相的溶解对于通过释放缓冲离子（如充分研究的碳酸盐和最常被忽视的磷酸氢盐）来调节pH是必不可少的。由于缺乏跨学科的词汇、知识和技术方法，控制离子释放动力学和程度的骨矿物质溶解机制仍然难以捉摸。PI的职业愿景是将材料科学，生物学和化学整合到骨骼生理系统（SaPS）的新科学中，以实现对生理环境与骨骼组成，结构和功能之间相互作用的革命性理解。骨矿物质是一种钙磷灰石，富含磷酸氢盐，这表明这种离子起着关键作用。PI的研究目标是通过开发一个可以应用先进的跨学科材料表征工具和研究方法的实验室，充分阐明骨骼成分之间的关系，特别是在磷酸氢盐离子含量，结构和生理酸/碱调节方面。体外、离体和体内骨骼模型将用于检查磷酸氢盐如何影响骨和骨矿物质的（1）缓冲响应、（2）晶体结构和（3）功能力学，以阐明磷酸氢盐介导的溶解及其与骨结构性质关系和功能的关系。将仿生骨磷灰石和个体骨暴露于具有不同pH值的模拟体液中，以测量骨矿物质组成对pH调节的影响以及其离子交换能力。将通过X射线断层扫描和高能X射线衍射（XRD）检查这些模型以及生理pH降低的体内小鼠模型，以阐明降低的生理pH和磷酸氢盐含量对骨的宏观、微观和纳米结构的影响。最后，将结合XRD、数字图像相关和全骨弯曲的多尺度方法来探讨骨和骨矿物质的力学，以研究骨矿物质酸溶解引起的功能变化。所有三个模型中获得的分层数据将被整合到一个统一的模型中，该模型描述了骨矿物质组成、结构、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。

Non-technical abstract:This career program seeks to integrate materials science, biology, and chemistry to elucidate the role of hydrogen phosphate on the dissolution of bone, an important prototypical and ubiquitous biomaterial. This program applies multi-scale multi-model techniques to understand how hydrogen phosphate affects bone structure, composition, and function during dissolution. Bone provides structural support, but it also provides buffering ions like carbonate and hydrogen phosphate that are necessary to regulate changes in environmental acidity. Despite being essential for acid/base regulation, the mechanism by which bone mineral is dissolved remains unclear. This research program will establish the scientific foundation necessary to manipulate and produce complex buffering materials that can be used for environmental remediation as well as new treatments of acid/base diseases, like acidosis, improving the quality of life of millions of individuals. In addition, the investigator’s self-efficacy education program uses the psychology concept of self-efficacy to integrate research and education. By facilitating access to STEM environments, increasing participation through role modelling, and supporting students via mentoring the investigator will maximize the factors that build confidence through self-efficacy and promote involvement in STEM. STEM access will involve positive research experiences in the investigator’s lab for undergraduate, graduate, medical and dental students. “Biomaterials” and “Dance & Physics” classes will further engage these students in STEM didactic activities. The Society of Women Engineers will offer a platform for role modeling at K-12 and undergraduate levels. A scaffolded mentoring program will provide students with the support needed to successfully meet future professional challenges.Technical abstract:Bone is an extraordinarily complex biomaterial that fulfills biological, chemical, and mechanical roles. It provides obvious structural support but also regulates important biochemical and physiological processes including acid/base equilibrium. Dissolution of the ceramic phase of bone is essential for pH regulation via release of buffering ions like the well-studied carbonate and the mostly overlooked hydrogen phosphate. The mechanism of bone mineral dissolution, which controls the kinetics and extent of the ionic release, remains elusive due to lack of transdisciplinary vocabulary, knowledge, and technical approaches. The PI’s career vision is to integrate materials science, biology, and chemistry into a new science of skeletal & physiological systems (SaPS) to achieve a revolutionary understanding of the interplay between the physiological environment and bone composition, structure, and function. Bone mineral, a calcium apatite, is rich in hydrogen phosphate, suggesting that this ion plays a key role. The PIs research goal is to fully elucidate the relationship between skeletal composition, especially in terms of hydrogen phosphate ionic content, structure, and physiological acid/base regulation by developing a laboratory that can apply advanced transdisciplinary materials characterization tools and investigative methods. In vitro, ex vivo, and in vivo skeletal models will be used to examine how hydrogen phosphate affects the (1) buffering response, (2) crystal structure, and (3) functional mechanics of bone and bone mineral to unravel hydrogen phosphate--mediated dissolution and its relationship to bone structure property relations and function. Exposure of biomimetic bone apatite and individual bones to simulated body fluid with varying pHs will be employed to measure the effect of bone mineral composition on pH regulation as well as its capacity for ion exchange. These models as well as an in vivo murine model of decreased physiological pH will be examined via X-ray tomography and high-energy X-ray diffraction (XRD) to elucidate the effects of depressed physiological pH and hydrogen phosphate content on the macro-, micro-, and nano-structure of bone. Finally, mechanics of bone and bone mineral will be probed using a multi-scale approach combining XRD, digital image correlation, and whole bone bending to investigate functional changes induced by acid dissolution of bone mineral. Hierarchical data obtained across all three models will be integrated into a unified model describing the relationship between bone mineral composition, structure, and bone functionality in acidic environments.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.