Tissue Chip Models for Cardiovascular Development and Disease

心血管发育和疾病的组织芯片模型

• 批准号: 10335220
• 负责人: Palaniappan Sethu
• 金额: $ 42.52万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-20 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335220
• 关键词: 3-Dimensional; Address; Adult; Arrhythmia; Basic Science; Biological Models; Biomimetics; Blood Circulation; Calcium; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular Models; Cardiovascular system; Cell Culture System; Cells; Circadian Rhythms; Complex; Data; Development; Devices; Diastolic blood pressure; Disease; Disease model; Drug usage; Electrophysiology (science); Embryo; Embryonic Heart; Engineering; Evaluation; Exercise; FDA approved; Functional disorder; Growth; Heart; Heart Diseases; Heart Rate; Heart failure; Hip region structure; Human; Human body; Hyperplasia; Hypertension; Hypertrophy; Ischemia; Left; Metabolism; Modeling; Myocardial tissue; Myocardium; Organ; Pathologic; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Physiologic intraventricular pressure; Physiological; Process; Publications; Pump; Recreation; Research; Risk; Role; Stem Cell Research; Stimulus; Stress; Stretching; Structure; System; Systole; Testing; Time; Tissue Engineering; Tissue Microarray; Tissue Model; Tissue constructs; Tissues; Translational Research; Validation; Ventricular; Withdrawal; base; blood pump; cardiac tissue engineering; cardiogenesis; cell type; circadian pacemaker; congenital heart disorder; drug discovery; drug testing; functional adaptation; hemodynamics; human model; human subject; human tissue; in vivo; individual response; induced pluripotent stem cell derived cardiomyocytes; microphysiology system; model development; pre-clinical; pressure; response; stressor; success; three dimensional cell culture; tissue culture

PROJECT SUMMARY Human Tissue Chips that accurately mimic organ-level structure and function are essential building blocks for fully functional Human Microphysiological Systems (MPS) to recreate complex system-level interactions between various organs and tissues. Human MPS have great potential to revolutionize basic and translational research and provide platforms for drug testing and disease modeling with direct relevance to humans. Cardiac Tissue Chips are of particular importance as they can not only be used to model cardiovascular disease but also represent an essential component of any MPS platform used for drug discovery as drug induced cardiotoxicity (arrhythmia risk) is a major reason for pharmaceutical withdrawal of FDA approved drugs. Development of physiologically relevant models of the human myocardium is challenging due to the lack of appropriate human cell types and culture systems. Recent breakthroughs in stem cell research have resulted in human induced pluripotent stem cell derived cardiomyocytes (hiPS-CM) but these cells are immature in phenotype and differ from human adult cardiomyocytes in terms of electrophysiological function, calcium handling, metabolism, and contractile function. The heart is a dynamic organ responsible for maintaining systemic circulation and platforms to culture engineered tissue need to recreate pressure-volume changes associated with physiological or pathophysiological heart (pump) function. To address shortcomings with current Cardiac Tissue Chip platforms, we developed a biomimetic cardiac tissue model (BCTM) that can subject engineered 3D cardiac tissue to pressure-volume changes associated with the ventricular chamber. Using the BCTM, we generated new data that demonstrates our ability to: (1) recreate pressure-volume changes associated with embryonic heart development to accomplish early maturation of hiPS-CMs and (2) recreate pathological tissue remodeling associated with pressure and volume overload. To establish the BCTM as a powerful Cardiac Tissue Chip Model that can either be used independently as a model of cardiovascular development and disease, or integrated within MPS for drug discovery and testing, we hypothesize: “Establishment of physiologically relevant Human Cardiac Tissue Chip Models that can replicate in vivo –like structural remodeling and functional adaptation as seen during heart development, normal function, and disease requires culture of engineered cardiac tissue under pressure-volume changes associated with each of these conditions”. To test this hypothesis, we propose three independent aims that focus on differentiation and maturation of hiPS- CMs as a model of congenital heart disease, device-based approach to mitigate pathological cardiac tissue remodeling and evaluate the cardiomyocyte circadian clock in development and disease. Successful completion of this project will validate the BCTM as a relevant model of the human ventricle for cardiovascular disease modeling and for potential integration with MPS platforms.

项目概要 准确模仿器官水平结构和功能的人体组织芯片是 功能齐全的人体微生理系统 (MPS)，可重建复杂的系统级交互 人类 MPS 具有彻底改变基础和转化研究的巨大潜力。 并提供与人类心脏组织直接相关的药物测试和疾病建模平台。 芯片特别重要，因为它们不仅可以用于模拟心血管疾病，还可以用于模拟心血管疾病。 代表用于药物发现的任何 MPS 平台的重要组成部分，因为药物引起的心脏毒性 （心律失常风险）是 FDA 批准药物开发撤回的主要原因。 由于缺乏适当的人类心肌的生理相关模型是具有挑战性的 细胞类型和培养系统的最新突破导致了人类诱导。 多能干细胞衍生的心肌细胞（hiPS-CM），但这些细胞的表型不成熟并且不同 来自成人心肌细胞的电生理功能、钙处理、代谢和 心脏是一个负责维持全身循环和平台的动态器官。 培养工程组织需要重现与生理或生理相关的压力-体积变化 病理生理心脏（泵）功能 为了解决当前心脏组织芯片平台的缺点， 我们开发了一种仿生心脏组织模型 (BCTM)，可以对工程 3D 心脏组织进行 使用 BCTM，我们生成了与心室相关的压力-容积变化。 (1) 重现与胚胎心脏相关的压力-容积变化 开发以实现 hiPS-CM 的早期成熟和 (2) 重建病理组织重塑 建立 BCTM 作为强大的心脏组织芯片模型。 可以独立用作心血管发育和疾病的模型，也可以综合使用 在用于药物发现和测试的 MPS 中，我们勇敢地说：“建立生理相关的 可在体内复制的人体心脏组织芯片模型 - 类似结构重塑和功能 心脏发育、正常功能和疾病过程中所见的适应需要培养 工程心脏组织处于与这些条件相关的压力-体积变化下”。 为了检验这一假设，我们提出了三个独立的目标，重点关注 hiPS 的分化和成熟—— CM 作为先天性心脏病的模型，基于设备的方法来减轻病理性心脏组织 重塑并评估发育和疾病中的心肌细胞生物钟。 该项目将验证 BCTM 作为人类心室心血管疾病的相关模型 建模以及与 MPS 平台的潜在集成。