A HUMAN IPSC-BASED 3D MICROPHYSIOLOGICAL SYSTEM FOR MODELING CARDIAC DYSFUNCTION IN MICROGRAVITY

项目概要 太空飞行已被证明对心脏和心血管系统有负面影响。正如我们计划的那样 对于探索类任务，人类将在太空中度过更长的时间，例如载人飞船 火星任务中，太空飞行对心脏和心血管系统的潜在影响可能是 增加。此外，太空飞行对人体的影响似乎类似于加速衰老 过程。鉴于心脏病是美国所有成年人的头号杀手，了解 微重力的心源性影响可能有助于治疗数百万心脏病患者 在地球上。不幸的是，关于太空飞行对心血管系统的影响仍然未知 尤其是心脏。为了解决这个问题，我们将开发一个高通量的微生理模型 人类心肌，源自人类诱导多能干细胞 (hiPSC)，以研究效果 微重力对心脏组织结构和生理功能的影响。我们将把这个细胞源与 基于心脏特异性脱细胞细胞外基质（dECM）的导电复合支架 促进培养细胞的成熟。本研究期间开发的技术将促进 生成成熟的 3D 工程心脏组织，再现心脏的微结构和功能 人类心肌。使用该平台在国际空间站 (ISS) 上收集的数据将 更好地了解长期微重力如何影响人类的结构和功能 心。在该提案的 UG3 阶段，我们将评估心脏功能和生理学的差异 在正常重力和微重力环境下维持细胞之间的成熟。工程心脏组织 由 hiPSC 衍生的心肌细胞制成的 (EHT) 将在国际空间站飞行一个月并进行比较 到相同的地面控制。 EHT 收缩性的实时评估将通过一种新颖的方法来实现 基于磁力计的运动传感器阵列，促进实时和连续的功能评估 对机组人员的最低要求。进入UH3阶段，我们将重点评估小说 减轻微重力诱发的心肌病的治疗策略。我们将评估这两种药物 化合物和机械刺激干预措施，并单独和一致地分析每种干预措施的能力 改善太空中的心脏功能。这项研究的结果可以进一步加深我们对 地球上慢性心脏病的进展，并有助于推动新治疗策略的开发 对于这些令人衰弱的情况。

PROJECT SUMMARY Spaceflight has been shown to have a negative impact on the heart and the cardiovascular system. As we plan for exploration class missions that will see humans spend longer periods of time in space, such as in a manned missions to Mars, the potential impact of spaceflight on the heart and cardiovascular system will likely be increased. Additionally, the effects of spaceflight on the human body appear to mimic an accelerated aging process. Given that heart disease is the number one killer of all adults in the U.S., an understanding of the cardiogenic effects of microgravity may have implications for helping to treat millions of heart disease patients on Earth. Unfortunately, much is still unknown regarding the effect of spaceflight on the cardiovascular system and the heart in particular. To address this issue, we will develop a high-throughput microphysiological model of human cardiac muscle, derived from human induced pluripotent stem cells (hiPSCs), in order to study the effects of microgravity on cardiac tissue structure and physiological function. We will combine this cell source with a cardiac-specific decellularized extracellular matrix (dECM)-based electroconductive composite scaffold to promote the maturation of cultured cells. The technologies developed during this study will facilitate the generation of mature 3D engineered cardiac tissues that recapitulate the microarchitecture and function of human myocardium. The data collected using this platform aboard the International Space Station (ISS) will provide a better understanding of how prolonged microgravity affects the structure and function of the human heart. During the UG3 phase of this proposal, we will assess differences in cardiac function and physiological maturation between cells maintained in normal gravity and microgravity environments. Engineered heart tissues (EHTs) made from hiPSC-derived cardiomyocytes will be flown aboard the ISS for one month and be compared to identical ground controls. Real-time assessment of EHT contractility will be achieved via a novel magnetometer-based motion sensor array, facilitating real-time and continuous assessment of function with minimal demands from the flight crew. Progressing to the UH3 phase, we will focus on the assessment of novel therapeutic strategies with which to attenuate microgravity-induced cardiomyopathy. We will assess both drug compounds and mechanical stimulation interventions and analyze each in isolation and in concert for their ability to improve cardiac function in space. The outcomes of this research could further improve our understanding of the progression of chronic heart diseases on Earth, and help drive the development of new therapeutic strategies for these debilitating conditions.