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.

项目摘要组织工程器官或功能性组织样合奏对我们对允许细胞在三个维度（3-D）中迁移，发展和成熟的细胞壁细分市场。常规的两个维（2-D）哺乳动物细胞培养并不代表形成形成的物理环境正常细胞功能的基础。 3-D环境促进各向同性细胞 - 细胞通信，提供结构基质支架的细胞外引导，并允许时空重塑。我们的具体兴趣是通过使用工程心脏来调查微重力对心脏功能的影响组织（EHT）。由于这些组织工程平台支持“底部”的多细胞体系结构提升方法，了解原始状态的心脏发展机制至关重要。尽管动物模型被广泛用于研究对治疗的生物学反应，但继承人与动物生物学之间的差异以及动物发展的可能性人类疾病限制了验证研究结果的能力。人类诱导的多能干细胞（HIPSC）已成为一种必不可少的工具，可以将细胞从胚胎状态驱动到任何体细胞类型。我们的实验室在产生HIPSC衍生的心肌细胞（HIPSC-CMS）和建模方面的重点和专业知识心肌病已经对几种罕见和常见的心力衰竭原因更深入地了解。到维持组织特异性的微环境，分离的细胞必须在物理相关的 3-D细胞外基质（ECM）。在第一阶段（UG3），我们将从健康患者中产生HIPSC-CM 属于潜水员种族群体（高加索人，西班牙裔和非裔美国人）。 HIPSC-CMS将用于制造我们特征良好的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的功能。因心脏弱化而改变心脏功能暴露于微重力的样品中的肌肉将与分子和电生理相匹配缺血性心肌病观察到的疾病模式。在第二阶段（UH3）中，特征良好微重力诱导的疾病表型将在心脏组织阵列（HTA）上翻译以筛选潜在的候选药物以高通量方式。拟议的研究将首次揭示关键功能性和分子差异，这些差异驱动EHT组件的心脏组织表型变化微重力的影响。

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.