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.

项目摘要精确模仿器官级结构和功能的人体组织芯片是必不可少的基础功能齐全的人类微生物生理系统（MPS），以重新创建复杂系统级别的相互作用各种器官和组织。人类国会议员具有彻底改变基本和翻译研究的巨大潜力并提供与人类直接相关的药物测试和疾病建模的平台。心脏组织芯片特别重要，因为它们不仅可以用于对心血管疾病进行建模，还可以使用代表用于药物发现的任何MPS平台的重要组成部分，作为药物诱导的心脏毒性（心律不齐风险）是戒断FDA批准药物的药物戒断的主要原因。发展人类心肌与生理相关的模型由于缺乏适当的人而具有挑战性细胞类型和培养系统。干细胞研究的最新突破导致了人类诱导的多能干细胞得出的心肌细胞（臀部CM），但这些细胞在表型中不成熟，并且不同从人类成人心肌细胞就电生理功能，钙处理，代谢和收缩功能。心脏是一个动态器官，负责维持全身循环和平台培养的组织需要重新创建与物理或物理或病理生理心脏（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），可以对3D心脏组织进行设计压力体积变化与心室腔室有关。使用BCTM，我们生成了新数据这证明了我们的能力：（1）重新创建与胚胎心脏相关的压力卷变化开发以实现臀部CM的早期成熟和（2）重现病理组织重塑与压力和体积超负荷相关。将BCTM建立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，或者整合在国会议员进行药物发现和测试中，我们假设：“建立身体相关的可以在体内复制的人类心脏组织芯片模型 - 例如结构重塑和功能适应在心脏发育，正常功能和疾病中所见，需要在压力体积下设计的心脏组织与每种条件中的每一个都会发生变化。为了检验这一假设，我们提出了三个独立的目标，这些目标集中于臀部的分化和成熟 - CMS作为先天性心脏病的模型，基于设备的方法来减轻病理心脏组织在发育和疾病中重塑和评估心肌细胞昼夜节律。成功完成该项目将验证BCTM作为心血管疾病的人类通风的相关模型建模并与MPS平台进行潜在集成。