Modeling Tyrosine Kinase Inhibitor-Induced Vascular Dysfunction Using Human iPSCs

项目总结 小分子酪氨酸激酶抑制剂(TKI)的开发使人的寿命急剧增加 白血病、癌症和黑色素瘤等癌症患者的预期。TKI抑制 高活性受体酪氨酸激酶(RTK)的激酶磷酸化活性，从而抑制 增强的细胞存活、增殖和迁移表型是癌症进展的标志。 然而，一些TKI与严重的血管副作用有关，如内皮毒性和高血压。 因此，必须建立准确评估TKI血管毒性的方法。在……里面 血管毒性和心血管疾病的体外模拟与成人血管一样令人感兴趣 内皮细胞很难在培养中长期分离和繁殖，动物模型经常 已证实不能预测患者的药物反应。特定于患者的人类诱导的多能干细胞- 来源的内皮细胞(IPSC-ECs)代表了一种新的心血管疾病建模技术。 人肺间充质干细胞已成功应用于肺源性心脏病的基本机制研究。 高血压和肥胖导致的内皮功能障碍。人类的IPSC-ECs也被用来筛选 用于各种心血管药物的疗效和毒性。事实上，我们的初步数据显示内皮细胞 接受TKIs治疗时患者特异性IPSC-ECs的功能障碍。在这里，在我们的多PI重新提交中，我们 假设人IPSC-ECs代表了一个新的研究机制和有效性的平台 基因组在调节TKI-VT中的作用。

PROJECT SUMMARY The development of small molecule tyrosine kinase inhibitors (TKIs) has led to a dramatic increase in life expectancy for patients suffering from cancers such as leukemias, carcinomas, and melanomas. TKIs inhibit the kinase phosphorylation activity of hyperactive receptor tyrosine kinases (RTK), thereby stymying the enhanced cell survival, proliferation, and migration phenotypes that are hallmarks of cancer progression. However, some TKIs are linked to severe vascular side effects such as endothelial toxicity and hypertension. Therefore, methods for accurately assessing TKI-induced vascular toxicity (TKI-VT) must be established. In vitro modeling of vascular toxicity and cardiovascular disease is of interest as human adult vascular endothelial cells are difficult to isolate and propagate long-term in culture, and animal models have often proven non-predictive of the drug response in patients. Patient-specific human induced pluripotent stem cell- derived endothelial cells (iPSC-ECs) represent a novel technology for modeling cardiovascular diseases. Human iPSC-ECs have already been successfully applied to understanding basic mechanisms of pulmonary hypertension and obesity-induced endothelial dysfunction. Human iPSC-ECs have also been used to screen for efficacy and toxicity of various cardiovascular drugs. Indeed, our preliminary data shows endothelial dysfunction in patient-specific iPSC-ECs when treated with TKIs. Here, in our multi-PI resubmission, we hypothesize that human iPSC-ECs represent a novel platform for studying the mechanisms and validity of genomic hits in regulating TKI-VT.