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Tissue Chip Models for Cardiovascular Development and Disease

心血管发育和疾病的组织芯片模型

基本信息

批准号：
10556353
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
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-20 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10556353
关键词：
3-Dimensional Address Adult Arrhythmia Basic Science Biological Models Biomimetics Calcium Cardiac Cardiac Myocytes Cardiotoxicity Cardiovascular Diseases Cardiovascular Models Cardiovascular system Cell Culture System Cells Circadian Rhythms Circulation 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 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

项目摘要

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.

项目总结精确模拟器官水平结构和功能的人体组织芯片是全功能人类微生理系统(MPS)重建复杂的系统级相互作用各种器官和组织。人类MPS具有使基础研究和翻译研究发生革命性变化的巨大潜力并为药物测试和与人类直接相关的疾病建模提供平台。心脏组织芯片特别重要，因为它们不仅可以用来模拟心血管疾病，而且还可以代表任何用于药物发现的MPS平台的基本组件，如药物引起的心脏毒性 (心律失常风险)是FDA批准的药物撤药的主要原因。发展中的由于缺乏合适的人，人体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。最近干细胞研究的突破导致人类诱导多能干细胞来源的心肌细胞(HIPS-CM)，但这些细胞表型不成熟，不同人成年心肌细胞的电生理功能、钙处理、代谢和收缩功能。心脏是一个充满活力的器官，负责维持全身循环和平台为了培养工程化组织，需要重建与生理或病理生理心脏(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)，它可以使工程化的3D心脏组织与脑室相关的压力-容量变化。使用BCTM，我们生成了新数据这表明我们有能力：(1)重建与胚胎心脏相关的压力-容量变化实现HIPS-CMS早期成熟和(2)重建病理性组织重塑的开发与压力和体积过载相关。建立功能强大的心脏组织芯片模型它既可以单独用作心血管发育和疾病的模型，也可以集成在用于药物发现和测试的MPS中，我们假设：“建立与生理相关的可在体内复制类结构重塑和功能的人心脏组织芯片模型在心脏发育、正常功能和疾病过程中看到的适应需要培养压力下的工程化心脏组织--与上述每种情况相关的体积变化“。为了验证这一假设，我们提出了三个独立的目标，专注于髋关节的分化和成熟- CMS作为先天性心脏病的模型，基于设备的方法减轻病理性心脏组织重构和评估发育和疾病中的心肌细胞生物钟。成功完成该项目将验证BCTM作为人体心血管疾病的相关模型建模和与MPS平台的潜在集成。