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

• 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
• 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

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 组织工程化器官或功能性组织样集合体有助于我们理解 允许细胞在三维（3-D）中迁移、发育和成熟的细胞小生境。传统的两个- 三维（2-D）哺乳动物细胞培养物并不代表形成细胞的生理环境。 正常细胞功能的基础。三维环境促进了各向同性的细胞间通信， 细胞外的指导，从结构基质支架，并允许时空重塑。我们的具体 我们的兴趣是研究微重力对心脏功能的影响，并使用工程心脏 组织（EHT）。由于这些组织工程平台从“底部”支持多细胞结构， 在“向上”的方法中，理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剂的生物学反应，但固有的免疫反应是不稳定的。 人类和动物生物学之间的差异，加上动物不可能发展出 人类疾病限制了验证研究结果的能力。人诱导多能干细胞（hiPSC） 已经成为将细胞从胚胎状态驱动到任何体细胞类型的不可或缺的工具。我们 实验室的重点和专业知识，在产生hiPSC衍生的心肌细胞（hiPSC-CM）和建模 心肌病已经对心力衰竭的几种罕见和常见原因有了更深入的了解。到 为了维持组织特异性微环境，解离的细胞必须在生理相关的环境中培养。 3-D细胞外基质（ECM）。在第一阶段（UG 3），我们将从健康患者中产生hiPSC-CM 属于不同的种族群体（高加索人，西班牙裔和非洲裔美国人）。hiPSC-CM将 用于制造我们充分表征的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。心脏衰弱导致的心脏功能改变 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， 在缺血性心肌病中观察到的疾病模式。在第二阶段（UH 3）， 微重力诱导的疾病表型将在心脏组织阵列（HTA）上进行翻译，以筛选 以高通量的方式筛选潜在的候选药物。这项研究将首次揭示 功能和分子差异驱动EHT组件上心脏组织的表型变化， 微重力的影响。

项目成果

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.

• DOI: 10.3389/fphar.2021.613837
• 发表时间: 2021
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Tu C;Cunningham NJ;Zhang M;Wu JC
• 通讯作者: Wu JC