Effect of Microgravity on Drug Responses Using Engineered Heart Tissues

微重力对工程心脏组织药物反应的影响

基本信息

批准号：
10670018
负责人：
Beth L Pruitt
金额：
$ 19.66万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-22 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10670018
关键词：
3-Dimensional Affect African American population Animal Model Animals Architecture Biological Biology Cardiac Myocytes Cardiomyopathies Cell Communication Cell Culture Techniques Cell physiology Cells Clinical Disease Drug Screening Electrophysiology (science)Environment Exposure to Extracellular Matrix Force of Gravity Heart Heart failure Hispanic Americans Human Laboratories Mammalian Cell Microgravity Modeling Molecular Myocardium Normal Cell Organ Patients Pattern Pharmaceutical Preparations Phase Phenotype Physiological Physiology Planet Earth Race Research Sampling Somatic Cell Therapeutic Time Tissue Engineering Tissue Microarray Tissues Translating blastomere structure cardiac tissue engineering cardiogenesis caucasian American cell type disease phenotype drug candidate ethnic diversity extracellular heart function human disease in vitro Model induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes insight interest ischemic cardiomyopathy racial diversity response scaffold space travel spatiotemporal three dimensional structure tool two-dimensional

项目摘要

PROJECT SUMMARY Tissue engineered organs or functional tissue-like ensembles contribute significantly to our understanding of cellular niches that allow cells to migrate, develop and mature in three dimensions (3-D). Conventional two- dimensional (2-D) mammalian cell culture does not represent the physiological environments that form the basis for normal cell function. A 3-D environment promotes isotropic cell-cell communications, provides extracellular guidance from structural matrix scaffolding, and allows spatiotemporal remodelling. Our specific interest is in investigating the effects of microgravity on heart function with the use of Engineered Heart Tissues (EHTs). Since these tissue engineering platforms support multicellular architecture from a ‘bottom- up’ approach, it is critical to understand the mechanisms of heart development from a primordial state. Although animal models are used widely to investigate biological responses to therapeutics, inherent differences between human and animal biology combined with the unlikelihood of animals developing a human disease limit the ability to validate research findings. Human induced pluripotent stem cells (hiPSCs) have emerged as an indispensable tool to drive cells from an embryonic state to any somatic cell type. Our laboratory’s focus and expertise in generating hiPSC-derived cardiomyocytes (hiPSC-CMs) and modelling of cardiomyopathies has yielded deeper insight into several rare and common causes of heart failure. To maintain a tissue-specific microenvironment, dissociated cells must be cultured in a physiologically relevant 3-D extracellular matrix (ECM). In the first phase (UG3), we will generate hiPSC-CMs from healthy patients belonging to diverse racial groups (Caucasians, Hispanics, and African Americans). The hiPSC-CMs will be used to fabricate our well-characterized EHT platforms, to understand cellular mechanisms that affect cardiac function both under microgravity and earth’s gravity. Alterations in cardiac function due to weakened heart muscles in the samples exposed to microgravity will be matched with molecular and electrophysiological disease patterns observed in ischemic cardiomyopathy. In the second phase (UH3), the well-characterized microgravity-induced disease phenotype will be translated on Heart Tissue Arrays (HTA) to screen for potential drug candidates in a high-throughput manner. The proposed study will for the first time reveal key functional and molecular differences that drive phenotypic changes in heart tissues on EHT assemblies under influence of microgravity.

项目概要组织工程器官或功能性类组织整体有助于我们理解细胞生态位允许细胞在三维 (3-D) 上迁移、发育和成熟。三维（2-D）哺乳动物细胞培养并不代表形成细胞的生理环境 3D 环境促进各向同性细胞间通讯，提供正常细胞功能的基础。来自结构矩阵支架的细胞外指导，并允许我们特定的时空重塑。兴趣是利用工程心脏来研究微重力对心脏功能的影响组织（EHT）由于这些组织工程平台从“底层”支持多细胞结构。向上”的方法，了解心脏从原始状态发育的机制至关重要。尽管动物模型被广泛用于研究对治疗的生物反应，但其固有的人类和动物之间的差异结合生物学以及动物不太可能发展出人类疾病限制了验证研究结果的能力。已成为驱动细胞从胚胎状态转变为任何体细胞类型的不可或缺的工具。实验室在生成 hiPSC 衍生心肌细胞 (hiPSC-CM) 和建模方面的重点和专业知识心肌病使人们对心力衰竭的几种罕见和常见原因有了更深入的了解。为了维持组织特异性的微环境，解离的细胞必须在生理相关的环境中培养在第一阶段 (UG3)，我们将从健康患者身上生成 hiPSC-CM。 hiPSC-CM 属于不同种族群体（白人、西班牙裔和非裔美国人）。用于构建我们特性良好的 EHT 平台，以了解影响心脏的细胞机制在微重力和地球重力下都能发挥作用由于心脏衰弱而导致心脏功能发生变化。暴露在微重力下的样本中的肌肉将与分子和电生理学相匹配在第二阶段（UH3）中观察到的缺血性心肌病的疾病模式。微重力诱发的疾病表型将在心脏组织阵列 (HTA) 上进行转化以筛选拟议的研究将首次揭示关键的潜在候选药物。驱动 EHT 组件上心脏组织表型变化的功能和分子差异微重力的影响。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Wafer-Scale Patterning of Protein Templates for Hydrogel Fabrication.

DOI：
10.3390/mi12111386
发表时间：
2021-11-12
期刊：
Micromachines
影响因子：
3.4
作者：
Kim AA;Castillo EA;Lane KV;Torres GV;Chirikian O;Wilson RE;Lance SA;Pardon G;Pruitt BL
通讯作者：
Pruitt BL

Human Induced Pluripotent Stem Cells as a Screening Platform for Drug-Induced Vascular Toxicity.