ISS: Microphysiologic Model of Human Cardiovascular Stiffness-Related Diseases in Microgravity

心血管疾病是现代世界最具破坏性的健康问题之一，心力衰竭和高血压影响了老龄人口的比例不断上升。心血管细胞和组织硬度增加是与正常衰老以及广泛的心血管疾病相关的特征。有趣的是，暴露在微重力下的宇航员也会经历主动脉硬化和心脏功能下降。因此，了解微重力下动脉硬化的过程和心脏后果可能会为与地球上衰老相关的心血管疾病提供新的见解。 这可能会导致改善地球上人类以及微重力下宇航员心血管健康的新方法。该研究项目的总体目标是利用器官芯片技术研究微重力条件下加速的心血管衰老。研究人员将部署一种新型的人体心血管系统器官芯片模型，称为微CV芯片，其中心脏和动脉结构将从人类多能干细胞中生长出来，并连接在一个功能性的微型循环系统中。这将允许除了细胞和组织生理学之外的流体运动和类器官刚度的建模。一组这些微型CV芯片将被送往国际空间站（ISS）体验微重力，在那里它们将在机器人实验室内进行监测和操作，以确定加速老化过程的任何迹象。最后，微型CV芯片将在地球上被取回并进行一系列彻底的生物测试。这些芯片将与留在地球上的对照芯片进行比较，此外还有从西奈山组织生物库获得的患者样本。该项目还将作为西奈山与纽约市几所学校正在进行的合作的一部分，用于教育和激励当地高中学生。该项目由三个科学目标支持。 首先，将表征心血管系统的多组织体外微流体人类类器官模型。 该微流体系统包括在内皮化循环系统中连接的单独的心脏和动脉类器官隔室。 它将能够自主心脏驱动的流量和动脉驱动的流体阻力变化，使其能够模拟动脉硬化和相关的心脏舒张功能障碍。 第二，一套微重力芯片将被送往国际空间站，以体验扩展的微重力。 将在国际空间站上使用创新的机器人压力控制和视频系统进行近实时地面监测，对动脉硬化和舒张性心脏功能障碍的表型标志物进行测试。 这将与飞行后组织学研究相结合。 最后，从国际空间站返回的样本的飞行后分析将通过多种分子生物学技术与地球上保存的对照样本进行比较，以确定新的疾病生物标志物和途径。 来自微心血管芯片的数据也将与通过西奈山心血管生物储存库和组学设施获得的患者样本数据进行比较，以评估心血管衰老新体外模型的优势和局限性。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

Cardiovascular disease is one of the most devastating health problems in the modern world, with heart failure and hypertension impacting a rising percentage of the aging population. Increased cardiovascular cell and tissue stiffness is a characteristic associated with normal aging as well as a wide range of cardiovascular diseases. Interestingly, astronauts exposed to microgravity also experience aortic stiffening and reduced cardiac function. Thus, understanding the process and cardiac consequences of arterial stiffening in microgravity may provide new insights into the related cardiovascular diseases associated with aging on Earth. This may then lead to new ways to improve cardiovascular health for humans on Earth as well as for astronauts in microgravity. The overall objective of this research project is to utilize organ-on-chip technology to study accelerated cardiovascular aging in microgravity. The researchers will deploy a novel, organ-on-chip model, known as a micro-CVchips, of the human cardiovascular system in which cardiac and arterial structures will be grown from human pluripotent stem cells and linked in a functional, miniature circulatory system. This will allow for the modeling of fluid movement and organoid stiffness in addition to cell and tissue physiology. A set of these micro-CVchips will be sent to the International Space Station (ISS) to experience microgravity, where they will be monitored and manipulated within a robotic laboratory to determine any signs of an accelerated aging process. Finally, the micro-CVchips will be retrieved and examined on Earth with a set of thorough biological tests. These chips will be compared to control chips that remained on Earth, in addition to patient samples obtained from a tissue biobank at Mount Sinai. This project will also be used as a vehicle to teach and inspire local high school students as part of an ongoing collaboration between Mount Sinai and several New York City schools. This project is supported by 3 scientific objectives. First, a multi-tissue in vitro microfluidic human organoid model of the cardiovascular system will be characterized. This microfluidic system includes separate cardiac and arterial organoid compartments linked in an endothelialized circulatory system. It will be capable of autonomous cardiac driven flow and arterial driven fluidic resistance changes, allowing it to model arterial stiffening and associated cardiac diastolic dysfunction. Second, a set of the micro-CVchips will be sent to the ISS to experience extended microgravity. Tests for phenotype markers of arterial stiffening and diastolic cardiac dysfunction will be made on board the ISS using an innovative robotic pressure control and video system for near-real-time terrestrial monitoring. This will be combined with post-flight histology studies. Finally, the post-flight analysis of the samples returned from the ISS will be compared to control samples maintained on Earth through numerous molecular biology techniques in order to identify novel disease biomarkers and pathways. The data from the micro-CVchip will also be compared to data obtained from patient samples obtained through the Mount Sinai Cardiovascular Biorepository and 'Omics Facility in order to evaluate the strengths and limitations of the new in vitro model of cardiovascular aging.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.