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.

骨质疏松症会导致骨骼随着年龄的增长而变得脆弱易碎，通常会在低力或跌倒的情况下导致骨折。众所周知，负重运动对骨骼有益，并能降低骨质疏松的风险。在太空中，微重力会导致许多生理变化--例如心脏和骨骼的去调理--并代表着一个独特的实验环境来检验生物假说--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丢失的结果有了深入的了解，但外加载荷如何影响细胞并导致骨丢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，并可以受到细胞硬度的调节。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联系起来。此外，还将比较在微重力条件下成骨细胞的发育和功能，以及在没有机械加压的情况下，是否将功能恢复到正常状态。回答这些问题将有助于加深对骨负荷变化如何导致骨丢失和骨质疏松症的理解，这将反过来支持改进的预防和治疗发展。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，为周六系列项目开发一个面向中学生的生物工程模块。本研究结合微流控设备、细胞生物学和生物工程系统，验证了在成骨细胞成熟的背景下，细胞力学调节YAP易位和骨形态发生蛋白(BMP)信号之间的串扰的假设。第一个目标将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。第二个目标是对成骨细胞施加机械压缩，以观察它们是否恢复了机械敏感性，如YAP/BMP信号恢复所证明的那样。该项目将实施一种微流体装置，自动测量微重力下细胞的机械性能，并将其与在地球上进行的测量进行比较。细胞张力对BMP信号和YAP易位的影响将在地球和国际空间站进行测量。在微重力条件下，还将检测机械压缩恢复3D球体中的成骨细胞BMP信号的能力。这项工作将提供新的生物工程平台，扩大国际空间站目前的研究能力。在细胞张力、YAP核质穿梭和BMP信号传递的关系方面将获得重要的见解。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。