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

项目摘要 太空飞行已被证明对心脏和心血管系统有负面影响。按照我们的计划 对于探索类任务，将看到人类在太空中度过更长的时间，例如在载人航天器中， 在火星任务中，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模拟了加速老化 过程鉴于心脏病是美国所有成年人的头号杀手，的理解 微重力对心脏的影响可能有助于治疗数百万心脏病患者 地球上不幸的是，关于航天对心血管系统的影响， 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， 来源于人诱导多能干细胞（hiPSC）的人心肌，以研究其作用 对心脏组织结构和生理功能的影响。我们将联合收割机这个细胞源与 基于心脏特异性脱细胞外基质（dECM）的生物相容性复合支架， 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工程化心脏组织，其重现了心脏的微结构和功能， 人体心肌使用国际空间站（ISS）上的这个平台收集的数据将 更好地了解长期微重力如何影响人体的结构和功能 心在本提案的UG3阶段，我们将评估心脏功能和生理学方面的差异。 在正常重力和微重力环境中维持的细胞之间的成熟。工程化心脏组织 由hiPSC衍生的心肌细胞制成的EHTs将在国际空间站上飞行一个月， 相同的地面控制。EHT收缩性的实时评估将通过一种新的 基于磁力计的运动传感器阵列，便于实时和连续评估功能， 机组人员的最低要求进入UH3阶段，我们将重点评估新的 减轻微重力诱导的心肌病的治疗策略。我们将评估两种药物 化合物和机械刺激干预，并分析每一个孤立和协调一致的能力， 来改善太空中的心脏功能这项研究的结果可以进一步提高我们对 地球上慢性心脏病的进展，并帮助推动新的治疗策略的发展 来治疗这些虚弱的病症

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.