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

• 批准号: 10646316
• 负责人: Wing H. WONG
• 金额: $ 67.6万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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/10646316
• 关键词: 3-Dimensional; Acute Coronary Event; Adhesions; Affect; African American population; Animal Model; Arteries; Asian population; Biological Assay; 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; Circulation; Citrates; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collagen Type I; Coronary; Data; Dissociation; Echocardiography; Endothelial Cells; Endothelium; Environment; Enzyme-Linked Immunosorbent Assay; Ethnic Origin; Exclusion; Extracellular Matrix; Force of Gravity; Functional disorder; Gene Targeting; Genome; Grant; Hispanic Populations; Histology; Human; Hydrogels; Hypertension; Inflammation; Journals; K-562; Knowledge; 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; Proliferating; 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 diversity; recruit; screening; self assembly; side effect; single-cell RNA sequencing; thrombogenesis; transcriptomics; tumor; vascular contributions; 3-Dimensional; Acute Coronary Event; Adhesions; Affect; African American population; Animal Model; Arteries; Asian population; Biological Assay; 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; Circulation; Citrates; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collagen Type I; Coronary; Data; Dissociation; Echocardiography; Endothelial Cells; Endothelium; Environment; Enzyme-Linked Immunosorbent Assay; Ethnic Origin; Exclusion; Extracellular Matrix; Force of Gravity; Functional disorder; Gene Targeting; Genome; Grant; Hispanic Populations; Histology; Human; Hydrogels; Hypertension; Inflammation; Journals; K-562; Knowledge; 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; Proliferating; 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 diversity; recruit; screening; self assembly; side effect; single-cell RNA sequencing; thrombogenesis; transcriptomics; tumor; vascular contributions

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.

项目摘要 酪氨酸激酶抑制剂（TKI）已显示可显着降低各种恶性肿瘤有关 在过去的二十年中的死亡率。但是，由于潜在的血管毒性而引起了人们的关注 这可能导致高血压，心肌梗塞，中风和周围动脉疾病。尽管如此 安全问题，对TKI诱导的血管毒性（TKI-VT）的机制知之甚少。到 克服这一挑战，我们建议利用人类的IPSC，最先进的多词方法和 CRISPR筛选研究TKI-VT的分子和细胞机制并识别可药物的目标 可以在动物模型中进一步测试。具体而言，在AIM 1中，我们将全面介绍人类诱导的 多能干细胞衍生的心脏周细胞（IPSC-PC），一种重要但很少探索的心脏细胞类型 定义TKI-VT的细胞机制。在AIM 2中，我们将评估TKI如何诱导细胞串扰的干扰 在IPSC-PC和IPSC衍生的内皮细胞（IPSC-EC）之间，通过在3D上执行集成幻数 片上的船只（VOC）型号。最后，在AIM 3中，我们将对经过TKI处理的IPSC-PCS进行CRISPR筛查，并进行 IPSC-EC鉴定潜在的可药物靶标并验证其在小鼠中的治疗功效。成功的 这些研究的完成将导致对TKI-VT发病机理的新机械见解，并有助于发展 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，该提议 将有助于定义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 心脏肿瘤之外的含义。