ISS: Cellular Mechanotransduction by Osteoblasts in Microgravity

ISS：微重力下成骨细胞的细胞力转导

• 批准号: 1927803
• 负责人: Allen Po-Chih Liu
• 金额: $ 40万
• 依托单位: Regents of the University of Michigan - Ann Arbor
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1927803&HistoricalAwards=false
• 关键词: ISS; Cellular; Mechanotransduction; Osteoblasts; Microgravity

Osteoporosis causes bones to become weak and brittle as individuals age and commonly leads to fracture with low forces or a fall. It is well appreciated that weight-bearing exercises are beneficial to the bones and lowers the risk of osteoporosis. In space, microgravity causes a number of physiological changes -- such as heart and bone deconditioning -- and represents a unique experimental environment to test biological hypotheses an environment that speeds up pathological changes. Despite a deep understanding of the outcomes of bone formation and bone loss in bone biomechanics, the mechanism of how applied loading affects the cells and causes bone loss and osteoporosis is not entirely clear. Recent research has suggested that a group of proteins, known as transcription factors, control gene expression in the nucleus of a cell and can be regulated by the stiffness of a cell. Leveraging the unique experimental environment on the International Space Station (ISS), this project will quantify the effect of microgravity on the stiffness of osteoblasts - bone forming cells - and relate this to the signaling that occurs due to key proteins. In addition, the development and function of osteoblasts in microgravity will be compared with and without the addition of mechanical compression in order to see if this returns function to a normal state. Answering these questions will support an increased understanding of how changes in bone loading cause bone loss and osteoporosis, which will in turn support improved prevention and treatment development. The research results will be shared broadly with the public through public talks, seminars, and publications. The PI will collaborate with the Detroit Area Pre-College Engineering Program to develop a bioengineering module for the Saturday Series program for middle school students. This research combines microfluidic devices, cell biology, and bioengineered systems to test the hypothesis that cell mechanics regulates the crosstalk between YAP translocation and Bone Morphogenic Protein (BMP) signaling in the context of osteoblast maturation. The first objective will determine if microgravity affects osteoblast mechanosensitivity by reduceing cell tension and thereby regulationg YAP/BMP crosstalk. The second objective will apply mechanical compression to osteoblasts to see if they recover their mechanosensitivity, as demonstrated by restored YAP/BMP signaling. The project will implement a microfluidic device to autonomously measure the mechanical properties of cells under microgravity and compare these with measurements performed on Earth. The effect of cell tension on BMP signaling and YAP translocation will be measured both on Earth and at the ISS. The ability for mechanical compression to restore BMP signaling of osteoblasts in 3D spheroids under microgravity will also be examined. This work will deliver new bioengineering platforms that will extend current research abilities on the ISS. Significant insights will be gained at the nexus of cell tension, YAP nucleocytoplasmic shuttling, and BMP signaling.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.

随着个体的年龄，骨质疏松症会导致骨骼变得脆弱和脆弱，通常导致低力或跌落的骨折。非常理解的是，承重运动对骨骼有益，并降低了骨质疏松症的风险。在太空中，微重力会导致许多生理变化（例如心脏和骨骼解析），并且代表了一个独特的实验环境，用于测试生物学假设的环境，以加快病理变化的速度。尽管对骨骼生物力学中骨形成和骨质流失的结果有深刻的了解，但施加负荷如何影响细胞并导致骨质流失和骨质疏松症的机制尚不完全清楚。最近的研究表明，一组被称为转录因子的蛋白质控制细胞核中的基因表达，可以通过细胞的刚度调节。利用国际空间站（ISS）上独特的实验环境，该项目将量化微重力对成骨细胞刚度的影响 - 骨形成细胞 - 并将其与由于关键蛋白质引起的信号传导相关联。 另外，将在微重力中进行成骨细胞的发展和功能，并在不增加机械压缩的情况下进行比较，以查看此函数是否返回正常状态。 回答这些问题将支持人们对骨负荷变化如何导致骨质流失和骨质疏松症的更多了解，这反过来又支持改善预防和治疗发展。 研究结果将通过公众谈判，研讨会和出版物与公众广泛分享。 PI将与底特律地区的大学前工程计划合作，为中学学生为周六系列计划开发生物工程模块。 这项研究结合了微流体设备，细胞生物学和生物工程系统，以测试细胞力学在成骨细胞成熟的背景下调节YAP易位与骨形态发生蛋白（BMP）信号之间的串扰的假设。 第一个目标将通过减少细胞张力，从而调节YAP/BMP串扰，从而确定微重力是否会影响成骨细胞的机械敏感性。 第二个目标将对成骨细胞进行机械压缩，以查看它们是否恢复其机械敏感性，如恢复的YAP/BMP信号传导所证明的那样。 该项目将实施一个微流体设备，以自主测量微重力下细胞的机械性能，并将其与在地球上执行的测量值进行比较。细胞张力对BMP信号传导和YAP易位的影响将在地球和ISS上测量。还将检查机械压缩恢复微重力下3D球体中成骨细胞的BMP信号传导的能力。这项工作将提供新的生物工程平台，以扩展ISS上的当前研究能力。在细胞张力，YAP核细胞质穿梭和BMP信号的联系中，将获得重要的见解。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优点和更广泛的影响审查标准来评估的。