ISS: Effect of Microgravity and Mechanical Deconditioning of Tissues on the Chromatin, Epigenetic Alteration, and Multiscale Biomechanics

这项NSF/CASIS在国际空间站(ISS)组织工程和机械生物学方面的合作惠及地球上的生命赠款将支持专注于了解组织力学的新研究，如骨骼肌、骨骼和心脏，以应对微重力暴露或长期解除条件。太空旅行的进步和在火星或月球上建立定居点将需要人类长期暴露在微重力环境中。对宇航员和小鼠模型的研究表明，微重力会对人体器官产生负面影响，但具体是如何发生的尚不清楚。此外，由于器官退化，地球上的患者可能会遭受骨骼和肌肉的损失。然而，推动这些变化的潜在机制仍不清楚。利用地面和国际空间站的小鼠实验，该项目将研究机械卸载和微重力如何触发细胞核内的变化，这些变化如何影响基因表达，以及最终如何影响器官功能。将开发新的药理干预措施，以减轻微重力和解除条件下发生的器官功能障碍。这项研究将通过建立一个基于向K-12学生传播空间生物力学知识的教育推广计划来补充。该项目试图发现组织水平的生物机械力和重力如何以细胞大小和组织类型依赖的方式维持染色质结构和基因表达。通过使用高分辨率显微镜、先进的机械特性、分子生物学测试、小鼠模型和模拟微重力实验等尖端技术，研究人员旨在回答机械生物学中的几个突出问题。具体地说，这项研究将调查：1)生物力学和引力如何协同定义染色质结构和调控基因表达；2)航天引起的染色质水平变化是否主要是由重力或太空中辐射暴露的改变驱动的；3)是否可以使用药物干预来减轻由航天和去条件引起的组织退化。这个项目将使研究人员能够在染色质机械生物学、表观遗传学和基因表达机制等领域推进现有知识的边界。总体而言，这项研究的结果可能会影响人类太空旅行的未来，并有助于制定有效解决地球上患者器官退化问题的战略。这一奖项反映了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。

This NSF/CASIS Collaboration on Tissue Engineering and Mechanobiology on the International Space Station (ISS) to Benefit Life on Earth grant will support new research focused on understanding the mechanics of tissues, such as skeletal muscle, bone, and heart, in response to microgravity exposure or prolonged deconditioning. Space travel advancements and establishing settlements on Mars or the Moon will require prolonged human exposure to microgravity. Studies on astronauts and mouse models have shown that microgravity can negatively affect organs in the body, but precisely how this happens is unknown. Additionally, patients on Earth can suffer from bone and muscle loss due to organ deconditioning. However, the underlying mechanisms driving these changes remain unclear. Utilizing experiments in mice on the ground and in International Space Station, this project will investigate how mechanical unloading and microgravity triggers changes inside the cell nucleus, how these changes influence gene expression, and how this ultimately affects organ function. Novel pharmacological interventions will be developed to mitigate organ dysfunction that occurs with microgravity and deconditioning. This research will be complemented by establishing an educational outreach program based on disseminating space biomechanics knowledge to K-12 students.This project seeks to discover how the biomechanical force at the tissue level and the gravitational force maintain the chromatin architecture and gene expression in a cell size and tissue type-dependent manner. By employing cutting-edge techniques such as high-resolution microscopy, advanced mechanical characterization, molecular biology assays, mouse models, and simulated microgravity experiments, the researchers aim to answer several outstanding questions in mechanobiology. Specifically, the study will investigate: 1) how biomechanical and gravitational forces collaboratively define chromatin architecture and regulate gene expression; 2) whether spaceflight-induced alterations in chromatin level changes is primarily driven by altered gravitational force or radiation exposure in space; and 3) whether pharmacological interventions can be used to mitigate tissue degeneration caused by spaceflight and deconditioning. This project will enable researchers to advance the boundaries of the existing knowledge in the fields of chromatin mechanobiology, epigenetics, and gene expression mechanisms. Overall, the outcome of this study might influence the future of human space travel and contribute to the development of strategies for effectively addressing organ deconditioning in patients on Earth.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.