Modeling Tyrosine Kinase Inhibitor-Induced Vascular Dysfunction Using Human iPSCs

项目摘要 小分子酪氨酸激酶抑制剂（TKI）的发展导致了生命的急剧增加 本发明提供了用于患有癌症如白血病、癌瘤和黑素瘤的患者的期望的药物组合物。TKI抑制 过度活跃的受体酪氨酸激酶（RTK）的激酶磷酸化活性，从而阻碍了 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诱导的血管毒性（TKI-VT）的方法。在 血管毒性和心血管疾病的体外建模是令人感兴趣的， 内皮细胞难以分离并在培养物中长期增殖，并且动物模型通常 被证明不能预测患者的药物反应。患者特异性人诱导多能干细胞- 衍生的内皮细胞（iPSC-EC）代表了用于模拟心血管疾病的新技术。 人类iPSC-ECs已经成功地应用于理解肺动脉高压的基本机制。 高血压和肥胖引起的内皮功能障碍。人类iPSC-EC也已用于筛选 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， 当用TKI治疗时，患者特异性iPSC-EC的功能障碍。在这里，在我们的多PI重新提交，我们 假设人iPSC-EC代表了研究以下机制和有效性的新平台： 基因组命中调节TKI-VT。

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.