GOALI: ISS Engineered Heart Tissue Chip to Assess Nanomedicine Strategies in a Spaceflight Model of Cardiac Aging

在美国，每五名死者中就有一人死于心脏病，而年龄是一个主要因素。有趣的是，太空飞行的独特环境条件，如微重力和暴露于银河宇宙辐射，与宇航员心血管疾病的恶化有关，这与老年人的心血管疾病相似。事实上，国际空间站上的宇航员在没有异常心跳史的情况下也会出现心律失常（心律不齐）。因此，太空飞行被提议用来模拟心血管老化。先前的研究发现，太空飞行引起的心脏功能障碍的直接决定因素是暴露于辐射和微重力下引起的高活性化学物质活性氧（ROS）的增加。高水平的活性氧以全身细胞的线粒体和细胞核为目标，诱导细胞功能障碍和DNA损伤——这是太空飞行和年龄引起的心脏病的标志。该研究小组旨在研究设计用于清除活性氧的纳米颗粒是否可以防止线粒体功能障碍，从而防止太空飞行引起的心脏异常。在这个项目中，研究小组将在太空和地球实验中部署一个工程心脏组织芯片，以测试纳米颗粒在功能心脏组织中的治疗效果。如果发现这种疗法对改善航天飞行期间的心脏功能有效，则可用于治疗一般人群中与年龄有关的心脏病。这是第一个在太空中测试纳米药物的项目。该项目还包括对青年科学家和学生的培训，并提供获得生物工程研究第一手经验的机会。该项目旨在确定清除活性氧（ROS）的纳米颗粒是否可以预防太空飞行诱导的线粒体功能障碍，从而防止太空飞行诱导的心肌病。人类诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）将在地球上生成，并成熟为生理相关的、功能性的3D工程心脏组织（EHTs）。将合成并优化具有线粒体和细胞核表面靶向基序的ros清除纳米颗粒来治疗EHTs。利用x射线辐射和模拟微重力随机定位机平台进行地面实验将有助于优化航天实验的条件和方案。在国际空间站（ISS）上，eht将被保存一个月，在此期间，它们将被清除ros的纳米颗粒处理。在太空飞行过程中，实时力测量将可用，以提供对eht状况的持续功能评估，并在飞行后在实验室进行完整的分析。实验结果包括收缩功能、DNA损伤、线粒体健康、细胞总ROS和钙处理。该项目将促进我们对活性氧在太空飞行诱导的心血管功能障碍中的作用的理解，以及活性氧清除纳米颗粒作为对策的潜力。此外，这些结果将为制定针对宇航员和地球上的老龄化人口心血管功能障碍的有效对策提供基础。（国际空间站的项目整合和运营将由空间科学促进中心的实施伙伴BioServe提供）。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。

Heart disease accounts for one in every five deaths in the United States, with age being a major contributing factor. Intriguingly, the unique environmental conditions of spaceflight, such as microgravity and exposure to galactic cosmic radiation, have been associated with cardiovascular deterioration in astronauts similar to that found in older individuals. In fact, cardiac arrhythmias (erratic heartbeats) have been noted in astronauts aboard the International Space Station with no prior history of abnormal heartbeats. Thus, spaceflight has been proposed to model cardiovascular aging. Previous studies found that a direct determinant of spaceflight-induced heart dysfunction is an increase in highly reactive chemicals known as reactive oxygen species (ROS) caused by exposure to radiation and microgravity. High levels of ROS target the mitochondria and nuclei in cells throughout the body inducing cellular dysfunction and DNA damage – hallmarks of spaceflight and age-induced heart disease. This research team aims to investigate if nanoparticles designed to scavenge ROS can prevent dysfunction in mitochondria, thereby protecting against spaceflight-induced cardiac abnormalities. In this project, the research team will deploy an engineered heart tissue chip in both space and Earth-bound experiments to test the therapeutic effects of nanoparticles in functioning heart tissues. If such a therapy is found to be efficacious in improving cardiac function during spaceflight, it may be used to treat age-related heart disease among the general population. This is the first project to test nanomedicines in space. This project also incorporates the training of young scientists and students and provides the opportunity to gain first-hand experience in bioengineering research.This project aims to determine if reactive oxygen species (ROS)-scavenging nanoparticles can prevent spaceflight-induced mitochondrial dysfunction, thus protecting against spaceflight-induced cardiomyopathies. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) will be generated on Earth and matured into physiologically relevant, functional 3D engineered heart tissues (EHTs). ROS-scavenging nanoparticles with surface targeting motifs for both mitochondria and the nucleus will be synthesized and optimized to treat the EHTs. Ground-based experiments using x-ray radiation and a simulated-microgravity random positioning machine platform will aid in optimizing conditions and protocols for the spaceflight experiment. Aboard the International Space Station (ISS), EHTs will be maintained for one month, during which time they will be treated with the ROS-scavenging nanoparticles. Real-time force measurements will be available during spaceflight to provide continuous functional assessment of the EHTs' condition with complete analyses to be conducted post-flight in the laboratory. The experimental outcomes include contractile function, DNA damage, mitochondrial health, total cellular ROS, and calcium handling. This project will advance our understanding of the role of ROS in spaceflight-induced cardiovascular dysfunction and the potential of ROS-scavenging nanoparticles as a countermeasure. Moreover, these results will provide a basis for developing effective countermeasures against cardiovascular dysfunction in both astronauts and the Earth-bound aging population. (Project integration and operation on the ISS will be provided by the Center for the Advancement of Science in Space’s implementation partner, BioServe).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.