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

ISS：微重力下人类心血管僵硬相关疾病的微生理模型

• 批准号: 1929028
• 负责人: Kevin Costa
• 金额: $ 49.99万
• 依托单位: Icahn School of Medicine at Mount Sinai
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1929028&HistoricalAwards=false
• 关键词: ISS; Microphysiologic; Model; Human; Cardiovascular

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.

心血管疾病是现代世界最具破坏性的健康问题之一，随着心力衰竭和高血压的影响，老年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，暴露在微重力环境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为研究地球上与衰老相关的心血管疾病提供新的见解。这可能会为地球上的人类以及微重力环境下的宇航员带来改善心血管健康的新方法。这个研究项目的总体目标是利用器官芯片技术来研究微重力下加速心血管老化。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，称为微型心血管芯片，其中心脏和动脉结构将从人类多能干细胞中生长出来，并连接在一个功能齐全的微型循环系统中。除了细胞和组织生理学之外，这将允许对流体运动和类器官刚度进行建模。一组这样的微型cvv芯片将被送到国际空间站（ISS）体验微重力，在那里，它们将在机器人实验室中进行监测和操作，以确定加速老化过程的任何迹象。最后，微芯片将被回收并在地球上进行一系列彻底的生物测试。这些芯片将与留在地球上的控制芯片以及从西奈山组织生物库获得的患者样本进行比较。该项目还将作为西奈山与纽约市几所学校持续合作的一部分，作为教育和激励当地高中生的工具。本项目由3个科学目标支持。首先，建立多组织体外微流控人心血管系统类器官模型。这种微流体系统包括独立的心脏和动脉类器官室，连接在内皮化的循环系统中。它将能够自主心脏驱动的血流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。其次，一组微型微重力芯片将被送往国际空间站，以体验扩展的微重力。动脉硬化和舒张性心功能障碍的表型标记测试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。这将与飞行后组织学研究相结合。最后，将对从国际空间站返回的样本进行飞行后分析，并通过多种分子生物学技术将其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cvchip的数据还将与通过西奈山心血管生物库和组学设施获得的患者样本数据进行比较，以评估新的体外心血管衰老模型的优势和局限性。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。