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

在美国，心脏病占死亡人数的五分之一，年龄是主要原因。有趣的是，太空飞行的独特环境条件，如微重力和银河宇宙辐射，与宇航员的心血管恶化有关，与老年人的情况类似。事实上，国际空间站上的宇航员已经注意到心律不齐(心跳不规律)，以前没有异常心跳的历史。因此，航天被提出用来模拟心血管衰老。以前的研究发现，航天引起的心脏功能障碍的一个直接决定因素是暴露在辐射和微重力下导致的高活性化学物质--活性氧物种(ROS)的增加。高水平的ROS针对全身细胞中的线粒体和细胞核，导致细胞功能障碍和DNA损伤--这是航天和老年性心脏病的特征。这个研究小组的目标是调查旨在清除ROS的纳米颗粒是否可以防止线粒体功能障碍，从而防止航天引起的心脏异常。在这个项目中，研究小组将在太空和地面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。如果这种疗法被发现在改善航天期间的心脏功能方面有效，它可能被用于治疗普通人群中与年龄相关的心脏病。这是第一个在太空测试纳米医学的项目。该项目还包括对年轻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防止航天引起的线粒体功能障碍，从而防止航天引起的心肌疾病。人类诱导多能干细胞来源的心肌细胞(hiPSC-CMS)将在地球上生成并成熟为具有生理功能的3D工程化心脏组织(EHTS)。将合成具有线粒体和细胞核表面靶向基序的清除ROS的纳米颗粒，并对其进行优化，以治疗EHTS。利用X射线辐射和模拟微重力随机定位机器平台进行的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，EHTS将被维持一个月，在此期间，它们将接受清除ROS的纳米颗粒的治疗。在航天飞行期间，将提供实时的力测量，以提供对EHTS状况的连续功能评估，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ROS在航天引起的心血管功能障碍中的作用以及清除ROS纳米颗粒作为对策的潜力的理解。此外，这些结果将为开发针对宇航员和地球上老龄化人口的心血管功能障碍的有效对策提供基础。(国际空间站上的项目整合和运作将由空间科学促进中心的实施伙伴BioServe提供)。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。

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.