Establishing an In Vitro Embryotoxicity Risk Classification System Based on Human Cardiac Organoid Model

建立基于人心脏类器官模型的体外胚胎毒性风险分类系统

基本信息

批准号：
10359793
负责人：
Zhen Ma
金额：
$ 44.67万
依托单位：
SYRACUSE UNIVERSITY
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：
2020-04-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10359793
关键词：
3-Dimensional Adopted Adverse effects Animal Experiments Animal Model Animals Antidepressive Agents Biochemistry Biological Biological Assay Biological Models Biometry Biophysics Brain Cardiac Cardiac development Cardiotoxicity Categories Cell Culture Techniques Cell Differentiation process Cell Maintenance Characteristics Chemicals Child Classification Complement Consumption Defect Development Discriminant Analysis Drug Compounding Drug Screening Drug toxicity Embryo Embryonic Development Evaluation Exposure to Fetal Development Fetus Generations Genetic Geometry Goals Heart Abnormalities Human In Vitro Incidence Limb Bud Modeling Morphogenesis Morphology Mus Organ Organogenesis Organoids Pattern Performance Pharmaceutical Preparations Pharmacologic Substance Physicians Physiological Physiology Predisposition Pregnancy Pregnant Women Process Regulation Risk Rodent Shapes Side Specific qualifier value Structural defect Structure System Testing Time Tissue Model Tissues Toxic effect Training Uncertainty United States Zebrafish base cardiogenesis cytotoxicity drug development drug discovery embryo culture embryonic stem cell heart function high risk human model improved in vitro Model in vitro testing in vivo in vivo evaluation induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes insight medication safety organ growth predictive modeling prenatal response restraint scaffold screening stem cell expansion stem cell growth stem cells three dimensional cell culture

项目摘要

Project Summary Currently, drug embryotoxicity risk for safe pregnancy is not well established, thus many pregnant women are exposed to the drugs with unknown effects on fetus development. Many drugs are still neither well understood regarding their effects on human organogenesis, nor is there a well-established human embryotoxicity drug screening platform available. Currently, human induced pluripotent stem cells (hiPSCs) have been proposed for human-relevant drug toxicity screening. However, the use of hiPSC maintenance and differentiation on 2D culture is not an ideal embryotoxicity assay due to their inability to predict the drug toxicity on 3D tissue morphogenesis, which potentially leads to the structural malformations manifested in late prenatal fetus development. With the emergent concept of stem cell organoids, these 3D cultures of developing tissues imply the similarity to the manner in which different organs establish their characteristic organization during development. Therefore, the overall goal of this proposal is to establish an in vitro hiPSC-based cardiac organoid model for embryotoxicity testing based on the drug effects on hiPSC growth, cardiac differentiation, and early heart formation, so we can establish a risk classification system for more precise assessment of human-specific drug effects on early embryonic development. To achieve this goal, we will pursue three specific aims. In Aim 1, we will optimize the cardiac organoid model by investigating the effects of biophysical confinement on the formation and function of cardiac organoids. In Aim 2, we will validate the cardiac organoid-based embryotoxicity assay by comparing to well-established standard zebrafish whole embryo culture assay. By testing a “training set” of chemicals with known embryotoxicity level, we will better calibrate the drug response from human cardiac organoids based on a variety of endpoint evaluation parameters. In Aim 3, we will establish a new biostatistical predictive model based on linear discriminant analysis for embryotoxicity risk classification. We envisage that this in vitro cardiac organoid model can improve traditional pharmaceutical screening for the drugs that will be administered during pregnancy.

项目概要目前，安全妊娠的药物胚胎毒性风险尚未明确，因此许多孕妇接触对胎儿发育影响未知的药物，许多药物仍然没有得到很好的了解。关于它们对人类器官发生的影响，也没有成熟的人类胚胎毒性药物目前，人类诱导多能干细胞（hiPSC）已被提议用于筛选平台。然而，使用 hiPSC 在 2D 上进行维持和分化。培养不是理想的胚胎毒性测定，因为它们无法预测 3D 组织上的药物毒性形态发生，可能导致产前胎儿晚期出现结构畸形随着干细胞类器官概念的出现，这些发育组织的 3D 培养物意味着。不同机关在不同时期建立其特有组织的方式的相似性因此，本提案的总体目标是建立体外基于 hiPSC 的心脏类器官。基于药物对 hiPSC 生长、心脏分化和早期发育的影响的胚胎毒性测试模型心脏形成，因此我们可以建立一个风险分类系统，以更精确地评估人类特定的药物对早期胚胎发育的影响为了实现这一目标，我们将追求三个具体目标：我们将通过研究生物物理限制对心脏类器官的影响来优化心脏类器官模型心脏类器官的形成和功能在目标 2 中，我们将验证基于心脏类器官的胚胎毒性。通过与完善的标准斑马鱼全胚胎培养测定进行比较通过测试“训练”。一组具有已知胚胎毒性水平的化学物质，我们将更好地校准人体心脏的药物反应在目标 3 中，我们将建立一个新的生物统计模型。我们设想基于线性判别分析的胚胎毒性风险分类预测模型。这种体外心脏类器官模型可以改善传统药物筛选怀孕期间施用。