Modeling Tyrosine Kinase Inhibitor-Induced Vascular Dysfunction Using Human iPSCs

使用人 iPSC 模拟酪氨酸激酶抑制剂诱导的血管功能障碍

基本信息

批准号：
10518663
负责人：
Lei Stanley Qi
金额：
$ 68.39万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10518663
关键词：
3-Dimensional Acute Coronary Event Adhesions Affect African American population Animal Model Arteries Asian population Biological Assay Blood Circulation Blood Pressure Blood Vessels Blood capillaries C57BL/6 Mouse CRISPR screen Cancer Patient Cancer cell line Candidate Disease Gene Cardiac Cardiovascular system Caucasians Cell Density Cell Proliferation Cell physiology Cells Citrates Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collagen Type I Coronary Data Echocardiography Endothelial Cells Endothelium Environment Enzyme-Linked Immunosorbent Assay Extracellular Matrix Force of Gravity Functional disorder Gene Targeting Genome Grant Hispanic Populations Histology Human Hydrogels Hypertension Inflammation Journals K-562 Knowledge Lead Length Libraries Malignant Neoplasms Mediating Methodology Methods Modeling Molecular Mus Myocardial Infarction Myography Nature Oncology Oxidative Stress Paper Pathogenesis Pathology Patients Pericytes Peripheral arterial disease Permeability Physiological Plasma Protocols documentation Publications Publishing Qi Reporting Resistance Role Safety Signal Pathway Stroke Testing Therapeutic Thrombosis Tissue Engineering Toxic effect Treatment Efficacy Tyrosine Kinase Inhibitor Vascular Diseases Vascular Endothelial Cell Whole Blood Wing cell type cohort druggable target endonuclease endothelial stem cell induced pluripotent stem cell induced pluripotent stem cell technology insight migration monocyte monolayer mortality mouse model multiple omics novel novel therapeutics pressure prevent racial and ethnic racial diversity recruit screening side effect single-cell RNA sequencing thrombogenesis transcriptomics tumor vascular contributions

项目摘要

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.

项目概要酪氨酸激酶抑制剂（TKI）已被证明可以显着减少多种与恶性肿瘤相关的疾病过去二十年的死亡率。然而，由于其潜在的血管毒性而引起了人们的担忧这可能导致高血压、心肌梗塞、中风和外周动脉疾病。尽管有这些出于安全考虑，人们对 TKI 诱导血管毒性 (TKI-VT) 的机制知之甚少。到为了克服这一挑战，我们建议利用人类 iPSC、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鉴定可药物靶点可以在动物模型中进一步测试。具体来说，在目标 1 中，我们将全面分析人类引起的多能干细胞衍生的心脏周细胞（iPSC-PC）是一种重要但很少被研究的心脏细胞类型，定义 TKI-VT 的细胞机制。在目标 2 中，我们将评估 TKI 如何诱导细胞串扰中断通过在 3D 上执行综合组学，在 iPSC-PC 和 iPSC 衍生内皮细胞 (iPSC-EC) 之间进行分析片上容器（VoC）模型。最后，在目标 3 中，我们将对 TKI 处理的 iPSC-PC 进行 CRISPR 筛选，并 iPSC-EC 用于识别潜在的药物靶标并验证其在小鼠中的治疗效果。成功的这些研究的完成将为 TKI-VT 发病机制带来新的机制见解，并有助于开发有前途的治疗策略可以预防和/或治疗癌症患者的 TKI-VT。此外，这项提案将有助于明确 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其影响超出了心脏肿瘤学的范畴。