A Human iPSC-based 3D Microphysiological System for Modeling Cardiac Dysfunction in Microgravity

基于人体 iPSC 的 3D 微生理系统，用于模拟微重力下的心脏功能障碍

• 批准号: 10434471
• 负责人: Deok-Ho Kim
• 金额: $ 8.04万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434471
• 关键词: 3-Dimensional; Address; Adult; Affect; Aging; Astronauts; Attention; Attenuated; Biological Assay; Biological Models; Biomimetics; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Categories; Cell Culture Techniques; Cells; Custom; Data; Data Management Resources; Data Set; Database Management Systems; Defect; Deposition; Deterioration; Development; Disease model; Earth orbit; Effectiveness; Ensure; Event; Exposure to; Extracellular Matrix; Functional disorder; Future; Goals; Grant; Health; Heart; Heart Diseases; Human; Human Resources; Human body; Impairment; International; Journals; Lead; Lipids; Long-Term Effects; Measurement; Measures; Mechanics; Mediating; Methodology; Methods; Microgravity; Microgravity Simulation; Mission; Mitochondria; Modeling; Myocardial dysfunction; Myocardium; Patients; Peer Review; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Planet Earth; Polymers; Population; Positioning Attribute; Preventive; Process; Publications; Quality Control; Reproducibility; Research; Resistance; Risk; Space Flight; Structure; System; Testing; Therapeutic; Therapeutic Intervention; Time; TimeLine; Tissues; Travel; Update; Work; absorption; base; biological adaptation to stress; cardiac tissue engineering; cardiovascular effects; combat; experimental analysis; experimental study; force sensor; human model; improved; induced pluripotent stem cell; mechanical force; microphysiology system; mitochondrial dysfunction; novel therapeutic intervention; novel therapeutics; polydimethylsiloxane; prevent; response; risk minimization; scaffold; space station; technology development; therapeutic candidate; time use

PROJECT SUMMARY Spaceflight has been shown to have negative impacts on the heart, with cardiac arrythmias observed in astronauts and the risk of adverse cardiac events increasing significantly in astronauts who traveled beyond low Earth orbit. Despite these observations, little is known about the underlying mechanistic reasons at the cell and tissue level. To address this, we developed a high-throughput microphysiological engineered heart tissue (EHT) model of human cardiac tissue, derived from human induced pluripotent stem cells (hiPSCs) to study the effects of spaceflight on cardiac cell and tissue structure and function. These EHTs are generated with a biomimetic extracellular matrix composition and stiffness with increased tissue conductivity, which improves overall tissue unction and is more analogous to adult human myocardium than many previous models. During the first phase of the parental grant, these EHTs were launched to the International Space Station (ISS), where contractile forces were measured in real time using a magnet-based force sensor system. Following 28 days in microgravity, tissue contractile function was impaired and mitochondrial dysfunction was observed. During the UH3 phase, a random positioning machine is being used to simulate microgravity and to test attenuating strategies. In this project, we will establish an in-house data management system to rigorously organize the datasets of the parental grant. These datasets will encompass control tissue function of physiologically-relevant tissues in our microphysiological system, tissues under real and simulated microgravity, and results of therapeutic screens on tissue function. It will also include information on strategies to prevent drug absorption in the polymeric components of our system. Once organized, the data will be compatible with, and deposited into, the Microphysiology Systems Database (MPS-Db), where it will be publicly available. Our data will expedite the development of technologies to combat the adverse cardiovascular effects caused by long-term exposure to microgravity. Additionally, the effects of spaceflight on the human body appear to mimic an accelerated aging process, including cardiac deterioration, in the general human population. We expect our data will also facilitate the development of technologies and therapies to attenuate cardiomyopathies on Earth.

项目总结 航天飞行已被证明对心脏有负面影响，在太空中观察到心律失常 宇航员和超过低空旅行的宇航员发生不良心脏事件的风险显著增加 地球轨道。尽管有这些观察，但对细胞和细胞的潜在机制原因知之甚少。 组织水平。为了解决这一问题，我们开发了一种高通量微生理工程心脏组织(Eht)。 以人心肌组织为模型，研究人诱导多能干细胞(HiPSCs)诱导分化的效果 航天对心肌细胞和组织结构和功能的影响。这些超高温超导是由一种仿生的 细胞外基质组成和硬度增加，组织导电性增加，从而改善整体组织 与许多以前的模型相比，它更接近于成人的心肌。在第一阶段 在父母的资助中，这些EHTS被发射到国际空间站(ISS)，在那里收缩 力是使用基于磁铁的力传感器系统实时测量的。在微重力状态下运行28天后， 组织收缩功能受损，线粒体功能障碍。在UH3阶段，一个 随机定位机正被用来模拟微重力和测试衰减策略。在这 项目，我们将建立一个内部数据管理系统，严格组织 父母补助。这些数据集将包括我们的 微生理系统，真实和模拟微重力下的组织，以及治疗筛选的结果 组织功能。它还将包括关于防止药物在聚合物中吸收的策略的信息 我们系统的组成部分。一旦组织好，数据将兼容并存储到 微生理学系统数据库(MPS-DB)，将在那里公开使用。我们的数据将加快 开发技术以对抗长期接触铅所造成的不良心血管影响 微重力。此外，太空飞行对人体的影响似乎类似于加速衰老。 在一般人群中，包括心脏恶化的过程。我们预计我们的数据也将有助于 地球上减轻心肌病的技术和治疗方法的发展。