ISS: Cellular Mechanotransduction by Osteoblasts in Microgravity

随着年龄的增长，骨质疏松症会导致骨骼变得脆弱和易碎，通常会导致轻微的力量或跌倒导致骨折。众所周知，负重运动对骨骼有益，可以降低患骨质疏松症的风险。在太空中，微重力会引起许多生理变化，比如心脏和骨骼的失调，这是一个独特的实验环境，可以测试生物学假设，一个加速病理变化的环境。尽管在骨生物力学中对骨形成和骨质流失的结果有深入的了解，但施加载荷如何影响细胞并导致骨质流失和骨质疏松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着细胞核中的基因表达，并可以通过细胞的硬度来调节。利用国际空间站（ISS）独特的实验环境，该项目将量化微重力对成骨细胞（骨形成细胞）硬度的影响，并将其与关键蛋白质产生的信号传导联系起来。此外，将比较微重力下成骨细胞的发育和功能，以及在没有机械压缩的情况下，以观察这是否会使功能恢复到正常状态。回答这些问题将有助于增加对骨负荷变化如何导致骨质流失和骨质疏松症的理解，这将反过来支持改进预防和治疗的发展。研究成果将通过公开讲座、研讨会和出版物与公众广泛分享。PI将与底特律地区大学预科工程项目合作，为中学生开发周六系列项目的生物工程模块。本研究结合微流体装置、细胞生物学和生物工程系统来验证细胞力学在成骨细胞成熟过程中调控YAP易位和骨形态发生蛋白（BMP）信号传导之间的串扰的假设。第一个目标是确定微重力是否通过降低细胞张力从而调节YAP/BMP串扰来影响成骨细胞的机械敏感性。第二个目标是通过YAP/BMP信号的恢复，对成骨细胞进行机械压迫，观察它们是否恢复了机械敏感性。该项目将实现一个微流体装置，以自主测量微重力下细胞的机械特性，并将这些测量结果与地球上的测量结果进行比较。细胞张力对BMP信号传导和YAP易位的影响将在地球和国际空间站上进行测量。机械压缩在微重力条件下恢复三维球体成骨细胞BMP信号的能力也将被研究。这项工作将提供新的生物工程平台，扩展国际空间站目前的研究能力。重要的见解将在细胞张力，YAP核胞质穿梭和BMP信号的关系中获得。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。

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.