Modeling Tyrosine Kinase Inhibitor-Induced Vascular Dysfunction Using Human iPSCs

项目总结 酪氨酸激酶抑制剂(TKI)已被证明可以显著减少多种与恶性肿瘤相关的 过去二十年的死亡率。然而，由于其潜在的血管毒性，人们对其提出了担忧。 这可能会导致高血压、心肌梗死、中风和外周动脉疾病。尽管如此 在安全性方面，TKI诱导的血管毒性(TKI-VT)的潜在机制尚不清楚。至 克服这一挑战，我们建议利用人类IPSCs、最先进的多组学方法，以及 CRISPR筛选研究TKI-VT的分子和细胞机制并寻找可用药靶点 这可以在动物模型中进一步测试。具体地说，在目标1中，我们将全面剖析人类诱导的 多能干细胞来源的心肌周细胞(IPSC-PC)是一种重要但很少被研究的心肌细胞类型，可 明确TKI-VT的细胞机制。在目标2中，我们将评估TKI如何引发中断的蜂窝串扰 IPSC-PC和IPSC来源的内皮细胞(IPSC-ECs)之间的关系 片上船只(VOC)模型。最后，在目标3中，我们将对经TKI处理的iPSC-PC进行CRISPR筛查，并 IPSC-ECs，以确定潜在的可用药靶点，并在小鼠身上验证其治疗效果。成功 这些研究的完成将为TKI-VT的发病机制带来新的机制见解，并有助于 有希望的治疗策略可以预防和/或治疗癌症患者的TKI-VT。此外，这项建议 将有助于确定TKI在血管病理生理学中的作用，这可能具有广泛的科学和临床意义 心脏肿瘤学以外的影响。

PROJECT SUMMARY Tyrosine kinase inhibitors (TKIs) have been shown to significantly decrease a variety of malignancy-related mortality in the past two decades. However, concerns have been raised due to their potential vascular toxicity that could lead to hypertension, myocardial infarction, stroke, and peripheral arterial diseases. Despite these safety concerns, the mechanisms underlying TKI-induced vascular toxicity (TKI-VT) are poorly understood. To overcome this challenge, we propose to leverage human iPSCs, state-of-the-art multi-omics methods, and CRISPR screening to investigate molecular and cellular mechanisms of TKI-VT and identify druggable targets that can be further tested in animal models. Specifically, in Aim 1, we will comprehensively profile human-induced pluripotent stem cell-derived cardiac pericytes (iPSC-PCs), an important but rarely explored cardiac cell type, to define cellular mechanisms of TKI-VT. In Aim 2, we will evaluate how TKIs induce disrupted cellular crosstalk between iPSC-PCs and iPSC-derived endothelial cells (iPSC-ECs) by performing integrative omics on a 3D vessel-on-chip (VoC) model. Finally, in Aim 3, we will perform CRISPR screening on TKI-treated iPSC-PCs and iPSC-ECs to identify potential druggable targets and validate their therapeutic efficacy in mice. Successful completion of these studies will lead to novel mechanistic insights into TKI-VT pathogenesis and help develop promising therapeutic strategies that can prevent and/or treat TKI-VT in cancer patients. Moreover, this proposal will help define the role of TKIs in vascular pathophysiology, which may have broad scientific and clinical implications beyond cardio-oncology.